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.

What is in this leaflet?

This leaflet answers some common questions about Fludarabine JUNO. It does not contain all of the available information. It does not take the place of talking to your doctor.

All medicines have risks and benefits. Your doctor has weighed the risks of using Fludarabine JUNO against the benefits it is expected to 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 using Fludarabine JUNO, ask your doctor.

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

What Fludarabine JUNO is used for and how it works

Fludarabine JUNO 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 JUNO works by hindering the production of new DNA. Therefore, when Fludarabine JUNO is taken up by the cancer cells it stops the growth of new cancer cells. It has been discovered that Fludarabine JUNO works especially well against some cancers of the white blood cells.

Before you are given Fludarabine JUNO

When you must not use it

You must not be given Fludarabine JUNO if any of the following apply to you:

  • Pregnancy or breast-feeding
  • Allergy (hypersensitivity) to any of the ingredients of this medicine
  • Your kidney function is severely reduced
  • The number of red blood cells is reduced due to a breaking down of these cells (hemolytic anemia)

The effects of Fludarabine JUNO have not been studied in children. It should not be used together with the leukaemia drug pentostatin.

Before you use it

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

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

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

Check with your doctor about any vaccinations you may need, because live vaccinations should be avoided during and after treatment with Fludarabine JUNO. It is not known whether Fludarabine JUNO decreases your fertility.

Fludarabine JUNO 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.

While using Fludarabine JUNO

When used in patients with acute leukemia at doses four times greater than the recommended dose for chronic lymphocytic leukemia (CLL), a third of patients experienced severe central nervous system effects including blindness, coma and death. Such effects have only rarely (coma and agitation) or uncommonly (confusion) been reported in patients who receive the recommended dose for CLL. However, you should mention to your doctor any unusual symptoms. The effect of long-term use of Fludarabine JUNO on the central nervous system is unknown.

The number of normal blood cells may also be reduced for periods of up to 12 months duration. You will have regular blood tests during treatment. On some occasions death has been reported in patients experiencing reductions in the number of normal blood cells.

Special regular checkups will be necessary in case you are over 75 years old, or your liver or kidneys do not work properly.

If you need a blood transfusion and you are being (or have been) treated with Fludarabine JUNO, you should mention this to the doctor.

If your disease is very severe, your body may not be able to get rid of all the waste products from the cells destroyed by Fludarabine JUNO. This may cause dehydration, kidney failure and heart problems. Your doctor will be aware of this and may give you other drugs to stop this happening.

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

Taking other medicines

This medicine should not be used with another drug called pentostatin (deoxycoformycin).

The effectiveness of Fludarabine JUNO may be reduced by medications containing dipyridamole and similiar substances. If you are taking any other medicines regularly, including medicines bought from a supermarket, health food store or pharmacy, tell your doctor.

How Fludarabine JUNO is given

How much is given

The dose of Fludarabine JUNO is calculated according to your body surface, which is calculated from your weight and height.

The recommended dose is 25 mg fludarabine phosphate/m2 body surface given daily for 5 consecutive days every 28 days by the intravenous route.

How it is given

Fludarabine JUNO is given as a 5 day treatment course which is repeated each month. The treatment involves injecting Fludarabine JUNO into a vein (often in the arm) once each day for 5 consecutive days. Your specialist, who should have experience with similar medications, will work out what dose is right for you.

How long it is given

Your doctor will decide how long to continue your treatment with Fludarabine JUNO.

Unwanted Effects

Like many leukaemia drugs Fludarabine JUNO is a very strong drug with many possible side effects, many of which can be very serious. Fludarabine JUNO can harm normal blood cells as well as the CLL blood cells, resulting in severe anaemia, abnormal bleeding and bruising and serious infections, especially pneumonia.

Fludarabine JUNO can also commonly cause:

  • fever and chills,
  • infection,
  • generally feeling unwell,
  • nausea and vomiting,
  • tiredness,
  • weakness,
  • numb or weak limbs,
  • build up of fluid in the body tissues,
  • visual problems,
  • loss of appetite,
  • inflammation of the lining of the mouth (stomatitis) and gut,
  • skin rashes.

An allergic reaction in the lungs, symptoms of which are difficulties in breathing and coughing can also rarely occur. If you experience any difficulty in breathing or have a cough tell your doctor immediately.

If you notice any unusual bruising, excessive bleeding after injury or if you develop signs of infections (e.g fever, chills, feeling unwell, pain), motor or visual disturbances, tell your doctor immediately.

Further side effects that have occurred in patients with chronic lymphatic leukaemia treated with Fludarabine JUNO are:

  • peripheral neuropathy (disturbances of the nervous system of your body);
  • diarrhoea,
  • mucositis
  • stomatitis and uncommonly gastrointestinal bleeding;
  • rare cases of haemorrhagic cystitis (inflammation with associated bleeding from the mucosa of the bladder);
  • tumour lysis syndrome.

If you notice a pain in your side, blood in your urine or that your stools are tar-coloured or covered with blood tell your doctor immediately.

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

Do not be alarmed by this list of possible side effects. You may not experience any of them. This is not a complete list of all possible side effects.

You should immediately report any side effects that you notice to your specialist or to the nursing staff.

Overdosage

The exact dose of Fludarabine JUNO is worked out by your specialist. The dose is determined by your weight and height.

Overdosage is unlikely to occur. In case of an overdose your doctor will stop the therapy and treat the symptoms.

After using Fludarabine JUNO

Storage

Fludarabine JUNO will usually be stored at the hospital below 25°C and protected from light.

Fludarabine JUNO should be stored where children cannot reach it or see it.

Fludarabine JUNO must not be used after the expiry date stated on the box and on the vial.

Disposal

Any unused medicine must be disposed appropriately by the medical staff.

Product Description

Fludarabine JUNO is a white or almost white powder in a glass vial. It is available as 50 mg/vial.

Each vial is for a single injection only. Fludarabine JUNO has to be reconstituted before use.

Ingredients

Fludarabine JUNO contains 50 mg Fludarabine phosphate. Other ingredients in the vial are mannitol and sodium hydroxide.

Sponsor

Juno Pharmaceuticals Pty Ltd
42 Kelso Street,
Cremorne,
VIC – 3121

Australian Registration Number:

Fludarabine JUNO fludarabine phosphate 50 mg powder for injection vial:
AUST R 147831

This leaflet was updated in May 2020.

Published by MIMS June 2020

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