INFORMATION FOR HEALTH PROFESSIONALS
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LEUKERAN Tablet 2mg is a brown, film-coated tablet that is round, normal, biconvex, and engraved with "GX EG3" on one face and "L" on the other face. Each tablet contains 2mg of chlorambucil.
Tablets.
LEUKERAN is indicated in the treatment of:-
LEUKERAN has a significant therapeutic effect in a proportion of patients with breast cancer.
THE RELEVANT LITERATURE SHOULD BE CONSULTED FOR FULL DETAILS OF THE TREATMENT SCHEDULES USED.
LEUKERAN is administered orally.
Used as a single agent in the palliative treatment of advanced disease a typical dosage is 0.2mg/kg/day for 4-8 weeks.
LEUKERAN is usually included in combination therapy and a number of regimes have been used.
LEUKERAN has been used as an alternative to nitrogen mustard with a reduction in toxicity but similar therapeutic results.
Used as a single agent the usual dosage is 0.1-0.2mg/kg/day for 4-8 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 lymphocytic lymphoma.
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 0.15mg/kg/day until the total leukocyte count has fallen to 10,000 per microL. Treatment may be resumed 4 weeks after the end of the first course and continued at a dosage of 0.1mg/kg/day.
In a proportion of patients usually after about 2 years of treatment, the blood leukocyte 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 per cent.
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.
Intermittent high dose therapy has been compared with daily LEUKERAN but no significant difference in therapeutic response or frequency of side effects was observed between the two treatment groups.
LEUKERAN is the treatment of choice in this indication.
Starting doses of 6-12mg daily until leucopenia occurs are recommended followed by 2-8mg daily indefinitely.
Used as a single agent a typical dosage is 0.2 mg/kg/day for 4-6 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 leukocyte count below 4,000/mm3.
In practice, maintenance courses tend to last 2-4 weeks with intervals of 2-6 weeks between each course.
Used as a single agent a typical dosage is 0.2 mg/kg bodyweight per day for 6 weeks.
LEUKERAN may be given in combination with prednisolone at a dose range of 14-20mg daily regardless of bodyweight, over 4-6 weeks provided there is no serious haemopoietic depression.
LEUKERAN may be given in combination with methotrexate, 5-fluorouracil, and prednisolone at a dosage of 5 to 7.5 mg/m2/day.
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.
In view of the seriousness of the indications there are no absolute contraindications.
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.
The handling of LEUKERAN Tablets should follow guidelines for the handling of cytotoxic agents according to prevailing local recommendations and/or regulations (for example, Royal Pharmaceutical Society of Great Britain Working Party on the Handling of Cytotoxic Drugs (Working Party Report, 1983, and subsequent Amendment, 1987)).
Provided the outer coating of the tablet is intact, there is no risk in handling LEUKERAN Tablets (Working Party Report, 1983). LEUKERAN Tablets should not be divided.
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 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 0.1mg/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.
Patients with evidence of impaired renal function should be carefully monitored as they are prone to additional myelosuppression associated with azotaemia.
The metabolism of LEUKERAN is still under investigation and consideration should be given to dose reduction in patients with gross hepatic dysfunction.
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 adverse reactions).
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.
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 400mg is necessary.
Varying degrees of recovery of spermatogenesis have been reported in patients with lymphoma following treatment with chlorambucil in total doses of 410-2600mg.
As with other cytotoxic agents LEUKERAN is potentially teratogenic.
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.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving LEUKERAN.
Mothers receiving LEUKERAN should not breastfeed.
No data.
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Special Warnings and Special Precautions For Use).
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.
The most common side effect is bone marrow suppression. Although bone marrow suppression frequently occurs, it is usually reversible if the chlorambucil is withdrawn early enough. However, irreversible bone marrow failure has been reported.
Actue secondary haematologic malignancies (especially leukaemia and myelodysplastic syndrome), particularly after long term treatment have occurred in patients treated with chlorambucil.
Leukopenia, neutropenia, thrombocytopenia and pancytopenia occurs very commonly while anaemia is commonly reported.
Gastro-intestinal disturbances such as nausea and vomiting, diarrhoea and oral ulceration occur infrequently. Other side effects may be encountered but usually only when the therapeutic dosage has been exceeded.
Severe interstitial pulmonary fibrosis has occasionally been reported in patients with chronic lymphocytic leukaemia on long term chlorambucil therapy. Pulmonary fibrosis may be reversible on withdrawal of chlorambucil.
Hepatoxicity and jaundice have been reported.
Allergic reactions to Leukeran such as urticaria and angioneurotic oedema have been rarely reported following initial or subsequent dosing. Skin rashes are uncommon but have on very rare occasions been reported to progress to serious conditions including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Other reported adverse reactions include fever, peripheral neuropathy, interstitial pneumonia and sterile cystitis.
Seizures have occurred in children with nephrotic syndrome treated with chlorambucil. Rare, focal and/or generalised seizures have been reported to occur in children and adults receiving therapeutic daily doses or high pulse dosing regimens of chlorambucil. Patients with a history of seizure disorder may be particularly susceptible.
Movement disorders including tremor, twitching and myoclonia in the absence of convulsions have also been reported.
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 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 2 strands of helical DNA and subsequent interference with replication.
In a study of 12 patients administered chlorambucil 0.2mg/kg bodyweight orally, the mean dose adjusted maximum plasma concentration (492 ± 160ng/mL) occurred between 0.25 and 2 hours after administration. The mean (± SD) terminal plasma elimination half-life was 1.3 ± 0.5 hours.
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 agent is well absorbed after oral dosage.
The metabolism of chlorambucil in man appears to be similar to that in laboratory animals and involves S-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. In a study of 12 patients administered chlorambucil 0.2 mg/kg bodyweight orally, the mean dose adjusted -peak plasma concentration of PAAM (306 ± 73 ng/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.
As with other cytotoxic agents chlorambucil is mutagenic in in vitro and in vivo genotoxicity tests and carcinogenic in animals and humans.
In rats, chlorambucil has been shown to damage spermatogenesis and cause testicular atrophy.
Chlorambucil has been shown to induce development 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 4-20mg/kg. Chlorambucil has also been shown to induce renal abnormalities in the offspring of rats following a single intraperitoneal injection of 3-6mg/kg.
No data.
36 months.
Store between 2°C and 8°C in a dry place.
Bottles of 25 tablets.
The handling of LEUKERAN Tablets should follow guidelines for the handling of cytotoxic agents according to prevailing local recommendations and/or regulations (for example, Royal Pharmaceutical Society of Great Britain Working Party on the Handling of Cytotoxic Drugs (Working Party Report, 1983, and subsequent Amendment, 1987)).
LEUKERAN Tablets should not be divided. Provided the outer coating of the tablet is intact, there is no risk in handling LEUKERAN Tablets (Working Party Report, 1983).
Prescription Only Medicine
GlaxoSmithKline NZ Limited
Quay Tower
Cnr Albert & Customs Streets
Private Bag 106600
Downtown
Auckland
NEW ZEALAND
Telephone (09) 367 2900
Facsimile (09) 367 2506
Date: 08 November 2006
Issue: 10
LEUKERAN™ is a trade mark of the GlaxoSmithKline Group of Companies.