Consumer medicine information

LEUSTATIN Injection

Cladribine

BRAND INFORMATION

Brand name

Leustatin

Active ingredient

Cladribine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using LEUSTATIN Injection.

SUMMARY CMI

LEUSTATIN® Injection

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 LEUSTATIN Injection?

LEUSTATIN Injection contains the active ingredient cladribine. LEUSTATIN Injection is used to treat Chronic Lymphocytic Leukaemia where treatment with alkylating agents has failed and Hairy Cell Leukaemia. For more information, see Section 1. Why am I using LEUSTATIN Injection? in the full CMI.

2. What should I know before I use LEUSTATIN Injection?

Do not use if you have ever had an allergic reaction to LEUSTATIN Injection 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 LEUSTATIN Injection? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with LEUSTATIN Injection 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 LEUSTATIN Injection?

  • The usual dose for hairy cell leukaemia is 0.09 mg/kg of your body weight daily for 7 days.
  • The usual dose for chronic lymphocytic leukaemia is 0.12 mg/kg of your body weight daily for 5 days.
  • LEUSTATIN Injection is given as an infusion into a vein by a doctor or a nurse.

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

5. What should I know while using LEUSTATIN Injection?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using LEUSTATIN Injection
  • If you are about to start taking a new medicine, tell your doctor and pharmacist you are taking LEUSTATIN Injection
  • Tell your doctor if you become pregnant while being given LEUSTATIN Injection
  • Use effective contraception during treatment with LEUSTATIN Injection and for 6 months after your last dose
Things you should not do
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how LEUSTATIN Injection affects you.
Looking after your medicine
  • Store LEUSTATIN Injection in a cool dry place where the temperature is below 8°C and protected from light
  • Keep LEUSTATIN Injection in a place where children cannot reach

For more information, see Section 5. What should I know while using LEUSTATIN Injection? 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.) Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any very serious side effects which suggest infection; numbness and tingling, usually in the hands and feet. Tell your doctor if you experience blood poisoning, anaemia, allergic reactions, swollen runny eyes, itchy rash, skin rashes, confusion (including disorientation), liver disease, lung disease, or renal failure.

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

LEUSTATIN® Injection

Active ingredient: Cladribine

Consumer Medicine Information (CMI)

This leaflet provides important information about using LEUSTATIN Injection. 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 LEUSTATIN Injection.

Where to find information in this leaflet:

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

1. Why am I using LEUSTATIN Injection?

LEUSTATIN Injection contains the active ingredient cladribine. LEUSTATIN belongs to a group of medicines known as antimetabolites. It interferes with the production of, and kills, abnormal white blood cells that are causing the leukaemia.

LEUSTATIN Injection is used to treat Chronic Lymphocytic Leukaemia where treatment with alkylating agents has failed and Hairy Cell Leukaemia.

2. What should I know before I use LEUSTATIN Injection?

Warnings

Do not use LEUSTATIN Injection if:

  • you are allergic to cladribine, 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 breastfeeding.

Do not use LEUSTATIN Injection if the packaging is torn or shows signs of tampering. Do not use LEUSTATIN Injection beyond the expiry date (month and year) printed on the pack.

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition

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

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Talk to your doctor if you are trying to make you partner pregnant.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking or are given LEUSTATIN Injection.

Your doctor will advise you whether or not to have LEUSTATIN Injection or if you need to adjust the dose or adapt your 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.

Do not take vaccines prepared from live microorganisms or functional viruses, because they may increase your risk of infections.

Some medicines may interfere with LEUSTATIN Injection and affect how it works.

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

4. How do I use LEUSTATIN Injection?

How much to use

Adults

  • The usual dose for hairy cell leukaemia is 0.09 mg/kg of your body weight daily for 7 days.
  • The usual dose for chronic lymphocytic leukaemia is 0.12 mg/kg of your body weight daily for 5 days.
  • Follow the instructions provided and use LEUSTATIN Injection until your doctor tells you to stop.

How to use LEUSTATIN Injection

  • LEUSTATIN Injection is given as an infusion into a vein by a doctor or a nurse. The contents of the vial are added to a large volume of a sterile solution of sodium chloride. This diluted solution needs to be prepared under special conditions which your doctor or pharmacist can explain. Once diluted, the solution may be stored at 2-8°C for no more than 8 hours before use.
  • For Hairy Cell Leukaemia the diluted solution is infused usually over 24 hours. This is repeated daily for 7 days, to complete the treatment.
  • For Chronic Lymphocytic Leukaemia the diluted solution is infused over 2 hours. This is repeated daily for a total of 5 days. Further courses are then usually given at monthly intervals.
  • For Chronic Lymphocytic Leukaemia the diluted solution is infused over 2 hours. This is repeated daily for a total of 5 days. Further courses are then usually given at monthly intervals.
  • LEUSTATIN Injection is a cytotoxic agent and precautions are necessary when handling, preparing and administering it. The use of disposable gloves and protective garments is recommended. If LEUSTATIN Injection contacts the skin or mucous membranes, wash the involved surface immediately with copious amounts of water.

If you use too much LEUSTATIN Injection

As LEUSTATIN Injection is being given to you under the supervision of your doctor it is very unlikely you will receive too much. Your doctor or nurse will be closely observing you during this time.

If at some later time you feel really unwell and you think LEUSTATIN Injection may be responsible, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre by calling:
Australia: 13 11 26
New Zealand: 0800 764 766
  • 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 LEUSTATIN Injection?

Things you must do

  • Always follow our doctor's instructions carefully
  • Tell you doctor if you become pregnant while being given LEUSTATIN Injection.
  • If you are about to start taking a new medicine, tell your doctor and pharmacist that you are receiving LEUSTATIN Injection.
  • Use effective contraception during treatment with LEUSTATIN Injection, and for 6 months after the last dose of LEUSTATIN Injection.

Remind any doctor, dentist or pharmacist you visit that you are using LEUSTATIN Injection.

Things you should not do

  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how LEUSTATIN Injection affects you.

Looking after your medicine

  • Keep LEUSTATIN Injection in the pack until it is time to use it.
  • Keep LEUSTATIN Injection in a cool dry place where the temperature is below 8°C and protect from light.

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

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

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

Keep it where young children cannot reach it.

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.

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

Because of your condition, your blood may already be weakened so that you are more susceptible to infections, you may be tired because of anaemia and any cuts may take longer to clot and heal. Although LEUSTATIN Injection is selective and kills mainly the leukaemia cells, it may further weaken your blood before strengthening it.

Serious side effects

Serious side effectsWhat to do
Blood related:
  • serious bacterial infection of the blood (blood poisoning)
  • anaemia (illness resulting from the destruction of red blood cells)
Immune system related:
  • allergic reactions
  • swollen runny eyes
  • itchy rash
Brain related:
  • confusion, including disorientation
Organ related:
  • liver disease
  • lung disease
  • renal failure
Skin related:
  • red scaly widespread rash with bumps under the skin (including your skin folds, chest, abdomen, back and arms) and blisters accompanied by fever
  • blistering of the skin, mouth, eyes or genitals
  • sudden red patches and blisters, usually on the palms of hands, soles of feet, and face, with flat, round red 'targets'
  • flu-like symptoms and a rash on the face followed by an extended rash with a high temperature and enlarged lymph nodes
Tell your doctor if you experience any of these serious side effects.

Very serious side effects

Very serious side effectsWhat to do
Infection related
  • symptoms suggestive of infections; numbness and tingling, usually of the hands and feet
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these very 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 above may also occur in some people.

Because of the prolonged action of this drug on the body some side effects may occur after the treatment has beencompleted.

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 LEUSTATIN Injection contains

Active ingredient
(main ingredient)		cladribine, 10 mg in each 10 mL vial
Other ingredients
(inactive ingredients)

sodium chloride

phosphoric acid and/or dibasic sodium phosphate

Potential allergens-

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

What LEUSTATIN Injection looks like

LEUSTATIN Injection is presented as a clear colourless solution in a single dose boxed vial. Each pack contains 1 vial (AUST R 48000).

Who distributes LEUSTATIN Injection

Sponsor:

Atnahs Pharma Australia Pty Ltd
Level 10 / 10 Shelley Street, SYDNEY, NSW, 2000
Australia

Distributed in Australia by:

Clinect Pty Ltd
120-132 Atlantic Drive
Keysborough VIC 3173
Australia

Free call Australia: 1800 899 005

Distributed in New Zealand by:

Clinect NZ Pty Limited
C/- Ebos Group Limited
108 Wrights Road
Christchurch 8024
New Zealand

Free call New Zealand: 0800 138 803

This leaflet was prepared in June 2022

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Leustatin

Active ingredient

Cladribine

Schedule

S4

 

1 Name of Medicine

Cladribine.

2 Qualitative and Quantitative Composition

Each 10 mL of the injection contains 10 mg of cladribine.
Leustatin injection is a synthetic antineoplastic agent for continuous intravenous infusion.
Cladribine is a chlorinated purine nucleoside analogue. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Leustatin injection is a clear, colourless, sterile, preservative-free, isotonic solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Leustatin is indicated for the treatment of patients with hairy cell leukaemia (HCL).
It is also indicated for the treatment of patients with B-cell chronic lymphocytic leukaemia (CLL) in whom treatment with alkylating agents has failed.

4.2 Dose and Method of Administration

Usual dose.

HCL.

The recommended treatment for hairy cell leukaemia is a single course of Leustatin given by continuous infusion for 7 consecutive days at a dose of 0.09 mg/kg/day. Clinical experience is limited to these specific recommendations; deviation (e.g. use of higher doses or a longer duration of treatment) is not advised. If the patient does not respond to the initial course of Leustatin injection, it is unlikely that they will benefit from additional courses. Physicians should consider delaying or discontinuing the drug if neurotoxicity or renal toxicity occurs (see Section 4.4 Special Warnings and Precautions for Use).

CLL.

In patients with CLL, the recommended treatment consists of a continuous infusion of Leustatin injection for 2 hours on days 1 to 5 of a 28 day cycle at a dose of 0.12 mg/kg/day (4.8 mg/m2/day). It is recommended that Leustatin injection be administered in responding patients up to a maximum of 6 monthly cycles and that non-responding patients receive no more than 2 cycles of treatment.
Specific risk factors predisposing to increased toxicity from Leustatin have not been defined. However, in view of the known toxicities of agents of this class, it would be prudent to proceed carefully in those with renal insufficiency or severe bone marrow impairment of any aetiology. Patients should be monitored closely for haematologic and non-haematologic toxicity.

Preparation and administration of intravenous solutions.

Leustatin injection must be diluted with the designated diluent prior to administration. Since the drug product does not contain any microbial preservative or bacteriostatic agent, aseptic technique and proper environmental precautions must be observed in preparation of Leustatin solutions.
[Should the drug accidentally be given extravenously, local tissue damage is unlikely. If extravasation occurs, the administration should be stopped immediately and restarted in another vein. Other recommended local measures include elevating the arm and applying an ice pack to reduce swelling.]

HCL.

 To prepare a single daily dose: Leustatin injection should be passed through a sterile 0.22 micrometre disposable hydrophilic syringe filter prior to introduction into the infusion bag, prior to each daily infusion.
Add the calculated dose (0.09 mg/kg or 0.09 mL/kg) of Leustatin through the sterile filter to an infusion bag containing 100 to 500 mL of 0.9% sodium chloride injection, USP. Infuse continuously over 24 hours. Repeat daily for a total of 7 consecutive days. See Table 1.

CLL.

 Preparation of a single daily dose: Leustatin injection should be passed through a sterile 0.22 micrometre disposable hydrophilic syringe filter prior to introduction into the infusion bag, prior to each daily infusion.
Add the calculated dose (0.12 mg/kg or 4.8 mg/m2) of Leustatin injection through the sterile filter to an infusion bag containing 100 mL or 500 mL of 0.9% sodium chloride USP. Infuse continuously over 2 hours. Repeat daily for a total of 5 consecutive days. The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine.
Since limited compatibility data are available, adherence to the recommended diluents is advised. The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine. Leustatin has been shown to be compatible with Viaflex infusion bags, Pharmacia Deltec Medication Cassettes and Millipore Millex-GV disposable filters. Solutions containing Leustatin should not be mixed with other intravenous drugs or additives or infused simultaneously via a common intravenous line, since compatibility testing has not been performed.
Care must be taken to assure the sterility of prepared solutions. Once diluted, solutions of Leustatin injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than 8 hours prior to start of administration. Vials of Leustatin are for single-use only. Any unused portion should be discarded in an appropriate manner (see Section 6.6 Special Precautions for Disposal).
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. A precipitate may occur during the exposure of Leustatin to low temperatures; it may be resolubilised by allowing the solution to warm naturally to room temperature and by shaking vigorously. Do not heat or microwave.

Chemical stability of vials and infusion solutions.

When stored in refrigerated conditions between 2° to 8°C (36° to 46°F) and protected from light, unopened vials of Leustatin injection are stable until the expiration date indicated on the package. Freezing does not adversely affect the solution. If freezing occurs, thaw naturally to room temperature. Do not heat or microwave. Once thawed, the vial of Leustatin injection is stable until expiry if refrigerated. Do not refreeze. Once diluted, solutions containing Leustatin injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than 8 hours prior to administration.

Handling and disposal.

The potential hazards associated with cytotoxic agents are well established and proper precautions should be taken when handling, preparing, and administering Leustatin. The use of disposable gloves and protective garments is recommended. If Leustatin contacts the skin or mucous membranes, wash the involved surface immediately with copious amounts of water. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Refer to your Institution's guidelines and all applicable state/local regulations for disposal of cytotoxic waste.

4.3 Contraindications

Leustatin is contraindicated in those patients who are hypersensitive to this drug or any of its components.
Leustatin is contraindicated during pregnancy and lactation.

4.4 Special Warnings and Precautions for Use

General.

Leustatin injection is a potent antineoplastic agent with potentially toxic side effects. It should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.
Patients undergoing therapy should be closely observed for signs of haematologic and non-haematologic toxicity (see Effects on laboratory tests). Patients who are or become Coombs positive should be monitored carefully for potential haemolysis.

CLL.

The weight of evidence suggests that a patient whose disease has progressed while treated with fludarabine is unlikely to respond to treatment with Leustatin injection, and therefore, use in such patients is not recommended.

Progressive multifocal leukoencephalopathy (PML).

Cases of progressive multifocal leukoencephalopathy (PML) including fatal ones have been reported following the use of Leustatin. Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural signs or symptoms. If PML is suspected then appropriate diagnostic evaluations should be undertaken and treatment suspended until PML is excluded (see Section 4.8 Adverse Effects (Undesirable Effects)).

Serious skin reactions.

An increased incidence of serious skin reactions (Stevens-Johnson syndrome (SJS) (see Section 4.8 Adverse Effects (Undesirable Effects)), toxic epidermal necrolysis (TEN), erythema multiforme, acute generalized exanthematous pustulosis) and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome has been observed in patients receiving Leustatin when administered concomitantly with antimicrobials and other drugs known to be associated with severe skin reactions (e.g. trimethoprim-sulfamethoxazole, allopurinol). It is recommended that patients be informed about the signs of serious skin reactions, and that use of Leustatin be discontinued at the first appearance of rash indicative of a serious skin reaction.

Neurotoxicity.

Serious neurological toxicity (including irreversible paraparesis and quadraparesis) has been reported in patients who received Leustatin injection by continuous infusion at high doses (4 to 9 times the recommended dose for hairy cell leukaemia) (see Section 4.9 Overdose). Neurological toxicity appears to be dose dependent. Severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens.

Bone marrow suppression.

Suppression of bone marrow function, including neutropenia, anaemia and thrombocytopenia should be anticipated. This is usually reversible and appears to be dose dependent, although prolonged lymphopenia up to 5 years following treatment has been reported. Proceed carefully in patients with severe bone marrow impairment of any aetiology since further suppression of bone marrow function should be anticipated.
Due to the prolonged immunosuppression associated with the use of nucleoside analogues like Leustatin, secondary malignancies are a potential risk. Primary haematological malignancies are also a risk factor for secondary malignancies.
HCL. During the first two weeks after treatment initiation, mean platelet count, absolute neutrophil count (ANC) and haemoglobin concentration declined, and then subsequently increased with normalisation of mean counts by day 15, week 5 and week 8, respectively. The myelosuppressive effects of Leustatin injection were most notable during the first month following treatment. In the first month, the incidence of severe neutropenia was 70%. Careful haematologic monitoring, especially during the first 4 to 8 weeks after treatment with Leustatin injection is recommended.

HCL (data based on a subset of 124 patients enrolled in K90-091).

Myelosuppression was frequently observed during the first month after starting treatment. Neutropenia (ANC < 0.5 x 109 L) was noted in 69% of patients, compared with 25% in whom it was present initially. Severe anaemia (haemoglobin < 85 g/L) developed in 41% of patients, compared with 12% initially and thrombocytopenia (platelets < 20 x 109/L) developed in 14% of patients compared with 5% in whom it was noted initially.
Treatment with Leustatin injection is associated with prolonged depression of CD4 lymphocyte counts and transient suppression of CD8 lymphocyte counts. [In a follow-up of 78 of the 124 patients enrolled in the clinical trials, prior to treatment the CD4 count was 0.766 x 109/L. The mean CD4 count nadir, which occurred 4 to 6 months following treatment was 0.272 x 109/L. Fifteen months after treatment the mean CD4 count remained below 0.50 x 109/L. Although CD8 counts decreased initially, increasing counts were observed by 9 months.] The clinical significance of the prolonged CD4 lymphopenia is unclear.
Prolonged bone marrow hypocellularity (< 35%) was observed. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or Leustatin injection toxicity.
CLL. During the first 2 cycles of Leustatin injection therapy, haemoglobin concentration, platelet count and absolute neutrophil count declined to a nadir usually observed in cycle 2. Careful haematologic monitoring is recommended throughout administration of Leustatin injection treatment.

CLL (Scripps study data based on a subset of 124 patients enrolled in L91-999).

Patients with CLL treated with Leustatin injection were more severely myelosuppressed prior to therapy than HCL patients. Increased myelosuppression was observed during Cycle 1 and Cycle 2 of therapy, reaching a nadir during cycle 2. The percentage of patients having a haemoglobin level below 85 g/L was 16.9% at baseline, 37.9% in Cycle 1 and 46.1% in Cycle 2. The percentage of patients with platelet counts below 20 x 109/L was 4.0% at baseline, 20.2% during Cycle 1 and 22.5% during Cycle 2. Absolute neutrophil count was below 0.5 x 109/L in 18.5% of patients at baseline, 56.5% in Cycle 1, 61.8% in Cycle 2, 59.3% in Cycle 3 and 55.9% in Cycle 4. Marked blood chemistry abnormalities noted during the study were pre-existing or were isolated abnormalities which resolved, or were associated with death due to the underlying disease.

Fever/infection.

Serious (e.g. respiratory infection, pneumonia and viral skin infections), including fatal infections (e.g. sepsis) were reported (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients with active infections should be treated for these underlying conditions prior to receiving Leustatin injection therapy.
Patients should be monitored closely for infections. Those presenting with herpes infections should be treated with acyclovir.
HCL. In clinical trials, fever was associated with the use of Leustatin injection in approximately 72% (89/124) of patients. Most febrile episodes occurred during the first month and were not associated with documented infection. In the first month, the incidence of infection was 31%.

HCL (data based on a subset of 124 patients enrolled in K90-091).

Fever was a frequently observed adverse event during the first month on study. [During the first month, 12% of patients experienced severe fever (i.e. greater than or equal to 40°C). Of the 124 patients studied, 11 were noted to have a documented infection in the month prior to treatment.] 31% febrile patients had a documented infection: [13.7% of patients had bacterial infections, 6.5% had viral and 6.5% had fungal infections. Seventy percent (70%) of these patients were treated empirically with antibiotics.]
Serious, including fatal, infections (e.g. septicaemia, pneumonia) were reported in 7% of all patients. [During the second month, the overall rate of documented infection was 8%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding Leustatin injection therapy.]
[Of the 124 hairy cell leukaemia patients entered in the two trials, there were 6 deaths following treatment; one death was due to infection, two to underlying cardiac disease and two to persistent hairy cell leukaemia with infectious complications. One patient died of progressive disease after receiving additional treatment with another chemotherapeutic agent.]
CLL. Pyrexia was reported in 23.6% of CLL patients during Cycle 1 of Leustatin injection therapy, and in less than 3% of patients during subsequent cycles. Forty of 123 patients (32.5%) reported at least one infection during cycle 1. Approximately 70% of patients had at least one infection during the overall study period of 6 years, including treatment and follow-up.

CLL (Scripps study data based in a subset of 124 patients enrolled in L91-999).

During Cycle 1 23.6% of patients experienced pyrexia, and 32.5% experienced at least one documented infection. Infections that occurred in 5% or more of the patients during Cycle 1 were: respiratory infection/inflammation (8.9%), pneumonia (7.3%), bacterial infection (5.6%) and viral skin infections (5.7%). In Cycles 2 through 9, 71.3% of the patients had at least one infection. Infections that occurred in 10% or more of patients were: pneumonia (28.7%), bacterial infection (21.8%), viral skin infection (20.8%), upper respiratory infection (12.9%), other intestinal infection/inflammation (12.9%), oral candidiasis (11.9%), urinary tract infection (11.9%) and other skin infections (11.9%). Overall, 72.4% of the patients had at least one infection during Leustatin injection therapy. Of these, 32.6% had been administered concomitant immunosuppressive therapy (prednisone).
Since the majority of fevers occurred in neutropenic patients, patients should be closely monitored during the first month of treatment and empiric antibiotics should be initiated as clinically indicated. Febrile events should be investigated with appropriate clinical diagnostic tests. Practitioners should carefully evaluate the risks and benefits of administering this drug to patients with active infections. Since fever may be accompanied by increased fluid loss, patients should be kept well hydrated (see Section 4.8 Adverse Effects (Undesirable Effects)).

Tumour lysis syndrome.

Hyperuricemia may occur as a result of rapid lysis of tumour cells, particularly in patients with large tumour burdens. Since cell lysis may begin as early as the first week of treatment caution should be exercised in those patients at risk of developing this complication. Rare cases of tumour lysis syndrome have been reported in patients with Leustatin with other haematological malignancies. Allopurinol and adequate hydration should be considered for patients with initially high WBC to alleviate potential tumour lysis syndrome side effects of therapy.

Use in hepatic impairment.

As there are inadequate data on dosing of patients with hepatic insufficiency, caution is advised when administering the drug to such patients. As with other potent chemotherapeutic agents, monitoring of hepatic function should be performed as clinically indicated, especially in patients with underlying liver dysfunction.

Use in renal impairment.

Acute renal insufficiency has developed in some patients receiving high doses of Leustatin injection (see Section 4.9 Overdose). As there are inadequate data on dosing of patients with renal insufficiency, caution is advised when administering the drug to such patients. As with other potent chemotherapeutic agents, monitoring of renal function should be performed as clinically indicated, especially in patients with underlying kidney dysfunction. Physicians should consider delaying or discontinuing Leustatin if renal toxicity occurs.

Use in the elderly.

No data available.

Paediatric use.

Safety and effectiveness in children has not been established. In a Phase I study involving patients 1-21 years old with relapsed acute leukaemia, Leustatin was given by continuous intravenous infusion in doses ranging from 3 to 10.7 mg/m2/day for 5 days (one-half to twice the dose recommended in hairy cell leukaemia). In this study, the dose-limiting toxicity was severe myelosuppression with profound neutropenia and thrombocytopenia. At the highest dose (10.7 mg/m2/day), 3 of 7 patients developed irreversible myelosuppression and fatal systemic bacterial or fungal infections. No unique toxicities were noted in this study.

Effects on laboratory tests.

During and following treatment, the patient's haematologic profile should be monitored regularly to determine the degree of haematopoietic suppression. In the clinical studies, following reversible declines in all cell counts, the mean platelet count reached 100 x 109/L by Day 12, the mean absolute neutrophil count reached 1.5 x 109/L by Week 5 and the mean haemoglobin reached 120 g/L by Week 8. After peripheral counts have normalised, bone marrow aspiration and biopsy should be performed to confirm response to treatment with Leustatin. Febrile events should be investigated with appropriate laboratory and radiologic studies. Periodic assessment of renal function and hepatic function are recommended.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There are no known drug interactions with Leustatin. Caution should be exercised if Leustatin is administered following or in conjunction with other drugs known to cause myelosuppression or immunosuppression.
Due to increased risk of infection in the setting of immunosuppression with chemotherapy including Leustatin, it is not recommended to administer live attenuated vaccines to patients receiving Leustatin injection.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Cladribine causes suppression of rapidly proliferating cells including testicular cells, resulting in hypospermia and aspermia when administered intravenously or subcutaneously to mice and monkeys. Cladribine doses up to 8 mg/kg (25.6 mg/m2 SC had no effect on female fertility and reproductive performance in mice. The effect of cladribine on human fertility is unknown. Antineoplastic agents, such as cladribine, which interfere with DNA, RNA and protein synthesis, might be expected to have adverse effects on human gametogenesis.
Men being treated with Leustatin injection should be advised not to father a child up to 6 months after the last Leustatin dose.
(Category D)
Leustatin may cause foetal harm when administered to pregnant women as it is teratogenic in animals. Treatment of pregnant mice during the period of organogenesis was associated with a significant increase in foetal variations at the dose of 1.5 mg/kg/day intravenously, and increased resorptions, reduced litter size and increased foetal malformations at 3.0 mg/kg/day. No foetal effects were seen in mice at 0.5 mg/kg/day. Foetal malformations were also observed in rabbits receiving 3.0 mg/kg/day intravenously during organogenesis, but not in rabbits receiving 1.0 mg/kg/day. An increased incidence of motor abnormalities in the offspring was additionally observed in mice treated with cladribine at doses up to 3.0 mg/kg/day during pregnancy and through the lactation period, although no effect was noted on other aspects of postnatal development, including reproductive function.
Leustatin is contraindicated in pregnancy (see Section 4.3 Contraindications). Women of childbearing potential must use effective contraception during treatment with Leustatin and for 6 months after the last dose of Leustatin. If the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the foetus. There are no adequate and well-controlled studies in pregnant women.
 It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cladribine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.
Leustatin is contraindicated in breastfeeding women (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

Given the patient's underlying medical condition, caution should be exercised when a patient is performing activities requiring substantial physical well-being while using Leustatin injection.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The clinical trials of cladribine were uncontrolled. Adverse events were assessed based on investigators opinions of relationship to cladribine, seriousness, severity, frequency, timing of cladribine administration and event, confounding factors and consistency with the pharmacology of cladribine. The events listed in this section are considered related to cladribine.
The CIOMS III frequency categories are: very common (≥ 10%), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%) and rare (≥ 0.01% and < 0.1%).

HCL.

See Table 2.

CLL.

See Table 3.

Postmarketing experience.

The following additional adverse reactions have been reported since the drug became commercially available. These adverse reactions have been reported primarily in patients who received multiple courses of Leustatin injection.

Infections and infestations.

Common: septic shock. Uncommon: opportunistic infections have occurred in the acute phase of treatment; progressive multifocal leukoencephalopathy (not known).

Blood and lymphatic system disorders.

Common: haemolytic anaemia (including autoimmune haemolytic anaemia). Uncommon: bone marrow suppression with prolonged pancytopenia; aplastic anaemia; hypereosinophilia; myelodysplastic syndrome.

Immune system disorders.

Common: hypersensitivity.

Metabolism and nutrition disorders.

Uncommon: tumour lysis syndrome; metabolic acidosis.

Psychiatric disorders.

Common: confusion (including disorientation).

Hepatobiliary disorders.

Uncommon: reversible, generally mild, increases in bilirubin; increases in transaminases; jaundice.

Nervous system disorders.

Uncommon: depressed level of consciousness; neurological toxicity including peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, paraparesis.

Eye disorders.

Common: conjunctivitis.

Cardiovascular disorders.

Uncommon: thrombophlebitis.

Respiratory, thoracic and mediastinal disorders.

Common: pulmonary interstitial infiltrates (including lung infiltration, interstitial lung disease, pneumonitis and pulmonary fibrosis).

Skin and subcutaneous tissue disorders.

Common: urticaria. Uncommon: Stevens-Johnson syndrome; toxic epidermal necrolysis; toxic skin eruption.

Renal and urinary disorders.

Common: renal failure (including renal failure acute, renal impairment).

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
In a Phase 1 study with 31 patients in which Leustatin injection was administered at high doses (4 to 9 times that recommended for hairy cell leukaemia) for 7-14 days in conjunction with cyclophosphamide and total body irradiation [as preparation for bone marrow transplantation], acute nephrotoxicity, delayed onset neurotoxicity, severe bone marrow suppression with neutropenia, anaemia and thrombocytopenia and gastrointestinal symptoms were reported.
Six patients (19%) developed manifestations of acute renal dysfunction/insufficiency (e.g. acidosis, anuria, elevated serum creatinine, etc.) within 7 to 13 days after starting treatment with Leustatin injection [5 of the affected patients required dialysis. Renal insufficiency was reversible in 2 (of 4) patients whose renal function had not recovered at the time of death. Several of these patients had also been treated with other medications having known nephrotoxic potential].
Eleven patients (35%) experienced delayed onset neurologic toxicity. In the majority, this was characterised by progressive irreversible motor weakness, of the upper and/or lower extremities (paraparesis/quadraparesis), noted 35 to 84 days after starting high dose therapy.
Axonal peripheral polyneuropathy was observed in a dose escalation study at the highest dose levels (approximately 4 times the recommended dose for hairy cell leukaemia) in patients not receiving cyclophosphamide or total body irradiation.
[Non-invasive neurological testing was consistent with demyelinating disease.]
There is no known specific antidote. It is not known whether the drug can be removed by dialysis or haemofiltration. Treatment of overdosage consists of discontinuation of Leustatin injection, careful observation and appropriate supportive measures.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Leustatin (cladribine) injection is a synthetic antineoplastic agent for continuous intravenous infusion.

Mechanism of action.

Cellular resistance and sensitivity.

The selective toxicity of cladribine towards certain normal and malignant lymphocyte and monocyte populations is based on the high ratio of deoxycytidine kinase (which phosphorylates it) to deoxynucleotidase (which dephosphorylates it). In these cells, cladribine, a purine nucleoside analogue, passively crosses the cell membrane. It is phosphorylated by deoxycytidine kinase to 2-chloro-2'-deoxy-β-D-adenosine monophosphate (2-CdAMP). Since cladribine is resistant to deamination by adenosine deaminase and there is little deoxynucleotide deaminase in lymphocytes and monocytes, 2-CdAMP accumulates intracellularly and is subsequently converted into the active triphosphate deoxynucleotide, 2-chloro-2'-deoxy-β-D-adenosine triphosphate (2-CdATP). It is postulated that cells with high deoxycytidine kinase and low deoxynucleotidase activities will be selectively killed by cladribine as toxic deoxynucleotides accumulate intracellularly.
Cells continuing high concentrations of deoxynucleotides are unable to properly repair single strand DNA breaks. The broken ends of DNA activate the enzyme poly(ADP-ribose) synthetase resulting in NAD and ATP depletion and disruption of cellular metabolism. There is evidence, also, that 2-CdATP is incorporated into the DNA of dividing cells, resulting in impairment of DNA synthesis. Thus, cladribine can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair.

Clinical trials.

In a clinical investigation, 17 patients with HCL and normal renal function were treated for 7 days with the recommended treatment regimen of Leustatin (0.09 mg/kg/day) by continuous intravenous infusion. A mean steady-state serum concentration of ~ 7 nanogram/mL was observed with a systemic clearance of ~ 600 mL/h/kg. Accumulation of 2-chloro-2'-deoxy-β-D-adenosine over the seven-day treatment period was not noted. In hairy cell leukaemia patients, there does not appear to be a relationship between serum concentrations of cladribine and ultimate clinical outcome.
In another study, 8 patients with haematologic malignancies received a two (2) hour infusion of Leustatin (0.094 mg/kg). The mean end-of-infusion plasma cladribine concentration was 58 ± 23 nanogram/mL. For 5 of these patients, the disappearance of cladribine could be described by either a biphasic or triphasic decline. For these patients with normal renal function, the mean terminal half-life was 5.4 hours. Mean values for clearance and steady-state volume of distribution were 933 ± 403 mL/h/kg and 4.32 ± 2.69 L/kg, respectively.
In an open, single arm, multicentre study conducted in UK, 34 patients with previously treated chronic lymphocytic leukaemia received up to 6 courses of Leustatin. Each course consisted of 5 consecutive days of treatment at 0.12 mg/kg/day, as a 2 hour daily i.v. infusion and courses were repeated at monthly intervals. Twenty-six patients were Binet Stage B or C with the remainder stage A but showing signs of progressive disease. Response, evaluated according to National Cancer Institute criteria was Complete Response (CR) 20.5%, partial response (PR) (56%). Two of seven CR patients relapsed after 64 and 65 weeks, eight of nineteen PR patients had a median duration of remission of 39 weeks before relapse.
Two single-center open studies of Leustatin have been conducted in patients with hairy cell leukaemia with evidence of active disease requiring therapy. In the study conducted at Centre A (Study A), 89 patients were treated with a single course of Leustatin given by continuous infusion for 7 days at a dose of 0.09 mg/kg/day. In the study conducted at Center B (Study B), 35 patients were treated with a 7-day continuous infusion of Leustatin injection at a comparable dose of 4 mg/m2/day. Responses were assessed using criteria consistent with accepted medical practice. Among patients evaluable for efficacy (N = 103), the complete response rates were 62% and 70% for Study A and Study B, respectively, yielding a combined complete response rate of 64%. Overall response rates (i.e. Complete plus Partial Responses) were 88% and 85% in Study A and Study B, respectively, for a combined overall response rate of 87%. See Table 4.
In these studies, 53% of the patients had received some prior therapy for hairy cell leukaemia including splenectomy, interferon and/or deoxycoformycin. Complete responses to Leustatin were seen in 73% of patients without any prior treatment compared with 56% of previously treated patients. The overall response rate for patients without any prior treatment was 94% compared with 82% for previously treated patients. The complete and overall response rates in non-splenectomised patients were 71% and 93%, respectively, compared to a complete response rate of 49% and an overall response rate of 76% in previously splenectomized patients. For patients previously treated with interferon, the complete response and overall response rates were 57% and 80%, respectively.
Response to Leustatin was similar for those initially responsive to interferon and those refractory to or intolerant of interferon therapy. See Table 5.
After a reversible decline, normalisation of peripheral blood counts (haemoglobin ≥ 120 g/L, platelets ≥ 100 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L) was achieved by 91% of evaluable patients. In patients achieving a complete response or partial response, the median times to normalisation of peripheral counts were 52 days (Range: 14 to 297) and 70 days (Range: 27 - 267), respectively. The mean platelet count normalised by Day 12, the mean ANC normalised by Week 5 and the mean haemoglobin normalised by Week 8. With normalisation of platelet count and haemoglobin, requirements for platelet and RBC transfusions were abolished after Months 1 and 2, respectively, in responding patients (see Table 6). Corresponding to normalisation of ANC, a trend toward a reduced incidence of infection was seen after the third month, when compared to the months immediately preceding Leustatin therapy.
The median time to complete response (i.e. absence of hairy cells in bone marrow and peripheral blood together with normalisation of peripheral blood parameters), measured from treatment start, was approximately 4 months. Since bone marrow aspiration and biopsy were frequently not performed at the time of peripheral blood normalisation, the median time to complete response may actually be shorter than that which was recorded. At the time of the data cut-off, the median duration of complete response was approximately 5 months and ranged up to 25 months. No relapses have been observed among patients achieving a complete response.

5.2 Pharmacokinetic Properties

Absorption.

Not applicable.

Distribution.

In patients with chronic B-CLL there was considerable variability in cladribine kinetics after two hour intravenous infusions of 0.14 mg/kg/day for 5 days. In one study (n = 13), the mean volume of distribution was 53.6 ± 23.7 L/m2, mean clearance 25.9 ± 7.8 L/h/m2 and mean terminal plasma elimination half-life, 9.9 ± 4.6 h, on day 5. In another study (n = 11 adults) mean plasma elimination half-life was 16.4 ± 7.1 h and mean elimination half-life of intracellular cladribine nucleotides 33.1 ± 18.3 h, on day 5.
Cladribine is bound approximately 20% to plasma proteins.

Metabolism.

There is variability in the metabolism and route of excretion of cladribine in man. In a study of 12 healthy male volunteers, given an intravenous infusion of cladribine 22-45 mg, 47% of the dose was excreted unchanged and 50% as metabolites in the urine. In 25 patients (16 male) with advanced solid tumours receiving cladribine 3.5-10.5 mg/m2/day for 5 days as a 2 hour intravenous infusion the urinary recovery of unchanged drug was 32% in the first 24 hours. Renal excretion accounted for only 18% of the elimination of cladribine over a 5 day intravenous infusion of 3.5-8.1 mg/m2/day in four patients aged 40-78 years with chronic lymphocytic leukaemia.

Elimination.

In a study of a small number of rats where radio labelled cladribine was administered, essentially all of the recoverable radioactivity was found in the urine. The effect of renal and hepatic impairment on the elimination of cladribine has not been investigated in humans.

5.3 Preclinical Safety Data

Genotoxicity.

As expected for compounds in this class, cladribine has been shown to cause DNA damage. In mammalian cells in culture cladribine has been shown to cause an imbalance of intracellular deoxyribonucleotide triphosphate pools. This imbalance is thought to result in the inhibition of DNA synthesis and repair, yielding DNA strand breaks and subsequently cell death. Cladribine caused chromosomal damage in Chinese hamster ovary (CHO) cells in vitro and in bone marrow cells (polychromatic erythrocytes) in vivo, and has been shown to inhibit DNA repair induced by gamma-radiation in lymphocyte cultures. Cladribine was not mutagenic in bacteria (Salmonella typhimurium and Escherichia coli) or Chinese hamster ovary cells, and did not induce unscheduled DNA synthesis (excision DNA repair) in primary rat hepatocyte cultures.

Carcinogenicity.

No animal carcinogenicity studies with cladribine have been conducted. However, given that the drug causes DNA damage, the carcinogenic potential of cladribine cannot be excluded.

6 Pharmaceutical Particulars

6.1 List of Excipients

The injection contains water for injections and sodium chloride. Phosphoric acid and/or dibasic sodium phosphate heptahydrate may have been added to adjust the pH.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store at 2° to 8°C. Refrigerate. Do not freeze. Protect from light.

6.5 Nature and Contents of Container

The injection is supplied in a clear type 1 glass vial with a chlorobutyl stopper in cartons of 1 vial.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

6.7 Physicochemical Properties

The chemical name for cladribine is 2-chloro-6-amino-9-(2-deoxy-β-D-erythropento-furanosyl) purine.
MW 285.7.

Chemical structure.


CAS number.

4291-63-8.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

Summary Table of Changes