Consumer medicine information

Leukeran

Chlorambucil

BRAND INFORMATION

Brand name

Leukeran

Active ingredient

Chlorambucil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Leukeran.

What is in this leaflet

This leaflet answers some common questions about Leukeran. It does not contain all 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 you taking Leukeran against the benefits they expect it will have for you.

If you have any concerns about taking this medicine ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Leukeran is used for

Leukeran contains chlorambucil as the active ingredient.

Leukeran belongs to a group of medicines called cytotoxics and is used to treat some types of cancer and certain blood disorders.

Ask your doctor if you have any questions about why Leukeran has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is only available with a doctor's prescription.

There is no evidence that it is addictive.

Before you take it

When you must not take it

Do not take Leukeran if you have ever had an allergic reaction to:

  • chlorambucil
  • any of the tablet ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue or any other parts of the body; rash, itching or hives on the skin.

Do not take Leukeran if you are planning to become pregnant or likely to father a child. Leukeran may harm the eggs and sperm so reliable contraceptive methods must be taken to avoid pregnancy whilst you or your partner is taking this medicine.

Do not take Leukeran if you are pregnant or breast feeding unless you and your doctor have discussed the risks and benefits involved.

Do not take Leukeran after the expiry date (EXP) printed on the bottle label.

Do not take it if the bottle shows signs of having been tampered with.

If you are not sure whether you should be taking Leukeran, talk to your doctor.

Before you start to take it

Tell your doctor if you are allergic to any other medicines or any foods, dyes or preservatives.

Tell your doctor if you have or have had any of the following conditions:

  • recently received a vaccination with a 'live' organism vaccine
  • recently received radiotherapy or chemotherapy treatment
  • are taking or likely to be taking other cytotoxic drugs
  • epilepsy, fits, convulsions or head trauma
  • liver or kidney disease.

If you have not told your doctor about any of the above, tell them before you start taking Leukeran.

Taking other medicines

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

Some medicines may be affected by Leukeran or may affect how well it works. You may need to take different amounts of your medicine or you may need to take different medicines. These include:

  • phenylbutazone
  • vaccinations with 'live' organism vaccines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking this medicine.

How to take it

How much to take

Your doctor will decide what dose and for how long you will be taking Leukeran. This depends on many factors such as your weight and your response to the treatment. Your doctor may change the dose and frequency of your medicine as your condition changes.

Your doctor may order regular blood tests while you are taking Leukeran in order to monitor your blood cell count and to change your dosage if necessary.

How to take it

Swallow the tablet whole with a glass of water.

Do not break, crush or chew the tablet.

When to take it

Take your medicine daily on an empty stomach, at least one hour before or three hours after meals. It is important to take your medicine regularly and at the same time each day

Ask your doctor or pharmacist if you are not sure of the instructions on the bottle label.

How long to take it

Continue taking Leukeran for as long as your doctor tells you.

If you forget to take it

Tell your doctor if you forget to take a dose.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much Leukeran. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking it

Things you must do

Take Leukeran exactly as your doctor has prescribed. Otherwise your doctor may think that it was not effective and change your treatment unnecessarily.

Tell any other doctors, dentists and pharmacists who are treating you that you are taking Leukeran, especially if you are being started on any new medicines.

Tell your doctor immediately if you become pregnant, are trying to become pregnant or trying to father a child while taking Leukeran.

If you are about to undergo surgery or an operation, tell your doctor or surgeon that you are taking Leukeran.

Things you must not do

Do not stop taking Leukeran or change the dose without first checking with your doctor.

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

Do not use Leukeran to treat any other complaints unless your doctor tells you to.

Things to be careful of

Do not break, crush or chew the tablet. Provided the outer coating of the tablet is intact, there is no risk in handling Leukeran tablets.

Be careful driving or operating machinery until you know how Leukeran affects you. It is unlikely that Leukeran will cause problems with your ability to drive a car or operate machinery. However, as with many other medicines, Leukeran may cause dizziness, drowsiness or tiredness in some people.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are taking Leukeran. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor to answer any questions you may have.

Tell your doctor as soon as possible if you notice any of the following:

  • frequent infections such as fever, sore throat or mouth ulcers
  • bruising or bleeding more easily than normal, nose bleeds
  • unusual tiredness, being short of breath, looking pale.

The above symptoms include the more common side effects of Leukeran which may result from the drop in production of bone marrow cells.

  • vomiting, diarrhoea
  • jaundice, a yellowing of the whites of the eyes or skin
  • rash
  • fits or convulsions
  • persistent cough or breathlessness
  • numbness or weakness of the arms or legs
  • in women, periods may stop
  • in men, sperm production may be reduced or stopped.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital if you notice any of the following allergic type symptoms:

  • wheezing
  • swelling of the lips and mouth
  • difficulty in breathing
  • severe rash
  • fainting.

Tell your doctor if you notice anything else that is making you feel unwell, even if you think the problems are not connected with this medicine and are not referred to in this leaflet. Other side effects not listed above may also occur in some people.

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

After taking it

Storage

Store Leukeran tablets in the refrigerator where the temperature is between 2 - 8°C. Do not freeze.

Keep it where young children cannot reach it.

Keep your tablets in the bottle until it is time to take them. If you take the medicine out of the bottle, it may not keep as well.

Disposal

If your doctor tells you to stop taking Leukeran or you find that the expiry date has passed, ask your pharmacist what to do with any tablets left over.

Product description

What it looks like

Leukeran tablets are brown, film-coated, round, biconvex tablets, engraved "GX EG3"on one side and "L" on the other.

Available in bottles of 25 tablets.

Ingredients

Active ingredient:
Each tablet contains 2 mg of chlorambucil.

Inactive ingredients:

  • cellulose-microcrystalline
  • lactose anhydrous
  • silica-colloidal anhydrous
  • stearic acid
  • opadry YS-1-16655-A Brown (PI) tablet coating system consisting of macrogol 400, hypromellose, titanium dioxide, iron oxide yellow (CI77492) and iron oxide red (CI77491).

Leukeran tablets do not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Aspen Pharmacare Australia Pty Limited
34-36 Chandos Street
St Leonards NSW 2065 Australia

Australian registration number: AUST R 73026

This leaflet was prepared in January 2012.

Published by MIMS April 2013

BRAND INFORMATION

Brand name

Leukeran

Active ingredient

Chlorambucil

Schedule

S4

 

1 Name of Medicine

Leukeran chlorambucil 2 mg tablet.

2 Qualitative and Quantitative Composition

Leukeran tablets contain 2 mg chlorambucil.
Chlorambucil is a white or off-white crystalline or granular powder. It is practically insoluble in water, freely soluble in acetone and in alcohol.

3 Pharmaceutical Form

Tablets, film-coated.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of Hodgkin's disease, certain forms of non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, Waldenstrom's macroglobulinaemia, advanced ovarian adenocarcinoma.
Leukeran has a significant effect in a proportion of patients with breast cancer.

4.2 Dose and Method of Administration

The literature should be consulted for full details of the treatment schedules used.
Leukeran is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.
Leukeran is administered orally, and should be taken daily on an empty stomach (at least one hour before meal or three hours after meal).

Hodgkin's disease.

Used as a single agent a typical dosage is 0.2 mg/kg/day for four to eight weeks. Leukeran is usually included in combination therapy and a number of regimens have been used. Leukeran may also be used as an alternative to nitrogen mustard with a reduction in toxicity but similar therapeutic results.

Non-Hodgkin's lymphoma.

Used as a single agent the usual dosage is 0.1 to 0.2 mg/kg/day for four to eight weeks initially; maintenance therapy is then given either by a reduced daily dosage or intermittent courses of treatment.
Leukeran is useful in the management of patients with advanced diffuse lymphocytic lymphoma and those who have relapsed after radiotherapy.
There is no significant difference in the overall response rate obtained with chlorambucil as a single agent and combination chemotherapy in patients with advanced non-Hodgkin's lymphoma.

Chronic lymphocytic leukaemia.

Treatment with Leukeran is usually started after the patient has developed symptoms or when there is evidence of impaired bone marrow function (but not marrow failure) as indicated by the peripheral blood count.
Initially Leukeran is given at a dosage of 0.15 mg/kg/day until the total leucocyte count has fallen to 10,000/microlitre. Treatment may be resumed 4 weeks after the end of the first course and continued at a dosage of 0.1 mg/kg/day.
In a proportion of patients, usually after about 2 years of treatment, the blood leucocyte count is reduced to the normal range, enlarged spleen and lymph nodes become impalpable and the proportion of lymphocytes in the bone marrow is reduced to less than 20%.
Patients with evidence of bone marrow failure should first be treated with prednisolone and evidence of marrow regeneration should be obtained before commencing treatment with Leukeran.

Waldenstrom's macroglobulinaemia.

Leukeran is the treatment of choice in this indication. Starting doses of 6 to 12 mg daily until leucopenia occurs are recommended followed by 2 to 8 mg daily indefinitely.

Ovarian carcinoma.

Used as a single agent a typical dosage is 0.2 mg/kg/day for four to six weeks. A dosage of 0.3 mg/kg/day has been given until leucopenia had been induced.
Maintenance dosage of 0.2 mg/kg/day has been given aiming to keep the total leucocyte count below 4000/mm3. In practice, maintenance courses tend to last 2 to 4 weeks with intervals of 2 to 6 weeks between each course.

Advanced breast cancer.

Used as a single agent a typical dosage is 0.2 mg/kg/day for six weeks. Leukeran may be given in combination with prednisolone at a dose range of 14 to 20 mg daily, regardless of bodyweight, over four to six weeks provided there is no serious haemopoietic depression. Leukeran may also be given in combination with methotrexate, 5-fluorouracil, and prednisolone at a dosage of 5 to 7.5 mg/m2/day.

Children.

Leukeran may be used in the management of Hodgkin's disease and non-Hodgkin's lymphomas in children. The dosage regimens are similar to those used in adults.

Special populations.

Hepatic impairment.

Patients with hepatic impairment should be closely monitored for signs and symptoms of toxicity. Since chlorambucil is primarily metabolized in the liver, dose reduction should be considered in patients with severe hepatic impairment. However, there are insufficient data in patients with hepatic impairment to provide a specific dosing recommendation.

Older people.

No specific studies have been carried out in older people. However, monitoring of renal or hepatic function is advised. In the event of impairment, caution should be exercised. While clinical experience has not revealed age-related differences in response, drug dosage should be titrated carefully in older patients, usually initiating therapy at the low end of the dosage range.

4.3 Contraindications

Chlorambucil should not be used in patients whose disease has demonstrated a prior resistance to the agent. Leukeran is contraindicated in patients with known hypersensitivity to chlorambucil or to any ingredient of the preparation.

4.4 Special Warnings and Precautions for Use

Leukeran is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.
Patients who will potentially have autologous stem cell transplantation should not be treated with chlorambucil long term.

Monitoring.

Since Leukeran is capable of producing irreversible bone marrow suppression, blood counts should be closely monitored in patients under treatment.
At therapeutic dosage Leukeran depresses lymphocytes and has less effect on neutrophil and platelet counts and on haemoglobin levels. Discontinuation of Leukeran is not necessary at the first sign of a fall in neutrophils but it must be remembered that the fall may continue for 10 days or more after the last dose.
Leukeran should not be given to patients who have recently undergone radiotherapy or received other cytotoxic agents. When lymphocytic infiltration of the bone marrow is present or the bone marrow is hypoplastic, the daily dose should not exceed 0.1 mg/kg bodyweight.
Children with nephrotic syndrome, patients prescribed high pulse dosing regimens and patients with a history of seizure disorder should be closely monitored following administration of Leukeran as they may have an increased risk of seizures. As with any potentially epileptogenic drug, caution should be exercised when administering chlorambucil to patients with a history of seizure disorder or head trauma, or who are receiving other potentially epileptogenic drugs.

Renal impairment.

Patients with evidence of impaired renal function should be carefully monitored as they are prone to additional myelosuppression associated with azotaemia.

Hepatic impairment.

The metabolism of Leukeran is still under investigation and consideration should be given to dose reduction in patients with gross hepatic dysfunction.

Effects on fertility.

Chlorambucil may cause suppression of ovarian function and amenorrhoea has been reported following chlorambucil therapy.
Azoospermia has been observed as a result of therapy with chlorambucil although it is estimated that a total dose of at least 400 mg is necessary.
Varying degrees of recovery of spermatogenesis have been reported in patients with lymphoma following treatment with chlorambucil in total doses of 410 to 2600 mg.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Leukeran.
In rats, chlorambucil has been shown to damage spermatogenesis and cause testicular atrophy.
(Category D)
As with other cytotoxic agents, Leukeran can produce spontaneous abortion, foetal loss and birth defects. The use of chlorambucil should be avoided whenever possible during pregnancy, particularly during the first trimester. In any individual case, the potential hazard to the foetus must be balanced against the expected benefit to the mother.
Mothers receiving Leukeran should not breastfeed.

Mutagenicity and carcinogenicity.

As with other cytotoxic agents chlorambucil is mutagenic in in vitro and in vivo genotoxicity tests and carcinogenic in animals and humans.
Chlorambucil has been shown to cause chromatid or chromosome damage in man. Acute secondary haematologic malignancies (especially leukaemia and myelodysplastic syndrome) have been reported, particularly after long term treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).
A comparison of patients with ovarian cancer who received alkylating agents with those who did not, showed that the use of alkylating agents, including chlorambucil, significantly increased the incidence of acute leukaemia.
Acute myelogenous leukaemia has been reported in a small proportion of patients receiving chlorambucil as long-term adjuvant therapy for breast cancer.
The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of chlorambucil.

Teratogenicity.

Chlorambucil has been shown to induce developmental abnormalities, such as short or kinky tail, microcephaly and exencephaly, digital abnormalities including ectro-, brachy-, syn- and polydactyly and long-bone abnormalities such as reduction in length, absence of one or more components, total absence of ossification sites in the embryo of mice and rats following a single oral administration of 4-20 mg/kg. Chlorambucil has also been shown to induce renal abnormalities in the offspring of rats following a single intraperitoneal injection of 3-6 mg/kg.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4 Special Warnings and Precautions for Use).
Purine nucleoside analogues (such as fludarabine, pentostatin and cladribine) increased the cytotoxicity of chlorambucil in vitro; however, the clinical significance of this finding is unknown.
Animal studies indicate that patients who receive phenylbutazone may require a reduction of the standard chlorambucil doses because of the possibility of enhanced chlorambucil toxicity.

4.6 Fertility, Pregnancy and Lactation

Please see Section 4.4 (Special Warnings and Precautions for Use).

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.
The following convention has been utilised for the classification of frequency: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). See Table 1.

4.9 Overdose

Treatment.

Reversible pancytopenia was the main finding of inadvertent overdoses of chlorambucil. Neurological toxicity ranging from agitated behaviour and ataxia to multiple grand mal seizures has also occurred. As there is no known antidote, the blood picture should be closely monitored and general supportive measures should be instituted, together with appropriate blood transfusion if necessary. Chlorambucil is not dialysable.
Further management should be as clinically indicated. For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Chlorambucil is an aromatic nitrogen mustard derivative which acts as a bifunctional alkylating agent. Alkylation takes place through the formation of a highly reactive ethylenimonium radical. A probable mode of action involves cross linkage of the ethylenimonium derivative between two strands of helical DNA and subsequent interference with replication.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

After oral administration of 14C-chlorambucil, maximum plasma radioactivity occurs between 40 and 70 minutes later. Studies have shown that chlorambucil disappears from the plasma with a mean terminal phase life of 1.5 hours and that its urinary excretion is low. A high level of urinary radioactivity after oral or intravenous administration of 14C-labelled chlorambucil indicates that the drug is rapidly and completely absorbed from the gastrointestinal tract after oral dosage.
In a study of 12 patients administered chlorambucil 0.2 mg/kg bodyweight orally, the mean dose adjusted maximum plasma concentration of chlorambucil (492 ± 160 nanogram/mL) occurred between 0.25 and 2 hours after administration. The mean (± SD) terminal plasma elimination half-life was 1.3 ± 0.5 hours.
The metabolism of chlorambucil in man appears to be similar to that in laboratory animals and involves β oxidation of the butyric acid side chain. Bis-2-chlorethyl-2(4-aminophenyl) acetic acid (phenylacetic acid mustard (PAAM)) is a major metabolite of chlorambucil. Chlorambucil and its metabolites are extensively bound to plasma and tissue proteins. In vitro, chlorambucil is 99% bound to plasma proteins, specifically albumin. In a study of 12 patients administered chlorambucil 0.2 mg/kg body weight orally, the mean dose adjusted peak plasma concentration of PAAM (306 ± 73 nanogram/mL) was reached within 1-3 hours. The mean terminal elimination plasma half-life was 1.8 ± 0.4 hours. The significant contribution of PAAM to the alkylating activity of the drug was evident as the mean area under the plasma concentration time curve (AUC) of PAAM was approximately 1.33 times greater than the AUC of chlorambucil.

5.3 Preclinical Safety Data

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Leukeran tablet contains the following excipients: lactose, microcrystalline cellulose, colloidal anhydrous silica, stearic acid, hypromellose, titanium dioxide, macrogol 400, iron oxide yellow (CI77492) and iron oxide red (CI77491).

6.2 Incompatibilities

No data available.

6.3 Shelf Life

36 months.

6.4 Special Precautions for Storage

Storage.

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

6.5 Nature and Contents of Container

Presentation.

Leukeran tablets are brown film-coated, round, biconvex tablets engraved "GX EG3" on one side and "L" on the other. They each contain 2 mg chlorambucil and are supplied in bottles of 25 and 50* tablets.
(*Not currently distributed in Australia).

6.6 Special Precautions for Disposal

Safe handling of Leukeran tablets.

The handling of Leukeran tablets should follow standard guidelines for the handling of cytotoxic drugs.
Provided the outer coating of the tablet is intact, there is no risk in handling Leukeran tablets. Leukeran tablets should not be divided.

6.7 Physicochemical Properties

The chemical name for chlorambucil is 4-[bis(2-chloroethyl)amino] benzenebutanoic acid, it has a molecular weight of 304.2, its molecular formula is C14H19Cl2NO2.

Chemical structure.

The chemical structure is:

CAS number.

305-03-3.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes