Aspen

Leukeran 2mg Film-coated Tablets

Each tablet contains 2mg of the active ingredient chlorambucil.

Each tablet also contains 67.65mg of lactose.

For a full list of excipients, see 6.1.

Film-coated tablet (Tablet)

Brown, film-coated, round, biconvex tablets engraved 'GX EG3' on one side and 'L' on the other.

Leukeran is indicated in the treatment of:-

- Hodgkin's disease;

- certain forms of non-Hodgkin's lymphoma;

- chronic lymphocytic leukaemia;

- Waldenstrom's macroglobulinaemia.

THE RELEVANT LITERATURE SHOULD BE CONSULTED FOR FULL DETAILS OF THE TREATMENT SCHEDULES USED.

Leukeran is administered orally.

Hodgkin's disease:-

Used as a single agent in the palliative treatment of advanced disease, a typical dosage is 0.2 mg/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.

Non-Hodgkin's lymphoma:-

Used as a single agent the usual dosage is 0.1-0.2 mg/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.

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 leukocyte count has fallen to 10,000 per μl. 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 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.

Waldenstrom's macroglobulinaema:-

Leukeran is the treatment of choice in this indication.

Starting doses of 6-12 mg daily until leucopenia occurs are recommended followed by 2-8 mg daily indefinitely.

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.

Use in the elderly:-

No specific studies have been carried out in the elderly, however, it may be advisable to monitor renal or hepatic function and if there is serious impairment then caution should be exercised.

Use in the management of patients with non-malignant disease.

Hypersensitivity to chlorambucil or to any of the excipients.

LEUKERAN IS AN ACTIVE CYTOTOXIC AGENT AND SHOULD ONLY BE ADMINISTERED UNDER THE DIRECTION OF A SPECIALIST ONCOLOGY SERVICE HAVING THE FACILITIES FOR REGULAR MONITORING OF CLINICAL BIOCHEMICAL AND HAEMATOLOGICAL EFFECTS DURING AND AFTER ADMINISTRATION.

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised individuals. Therefore, immunisations with live organism vaccines are not recommended.

Safe handling of Leukeran Tablets:- See 6.6 Instructions for Use/Handling.

Monitoring:-

Since Leukeran is capable of producing irreversible bone marrow suppression, blood counts should be closely monitored in patients under treatment. Total dosage in the region of 6.5mg/kg bodyweight is associated with the risk of irreversible bone marrow damage.

At therapeutic dosage Leukeran depresses lymphocytes and has less although progressive 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.

Chlorambucil should only be used with caution in patients with depressed bone narrow function or lymphocytic infiltration of same.

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 as 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.

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.

Mutagenicity and carcinogenicity:-

Chlorambucil has been shown to cause chromatid or chromosome damage in man and has been shown to be carcinogenic in animals.

The possibility of a similar effect should be borne in mind when designing the long-term management of the patient.

Acute secondary haematologic malignancies (especially leukaemia and myelodysplastic syndrome) have been reported, particularly after long term treatment (see section 4.8 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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Warnings and Precautions).

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.

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 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 410-2600 mg.

Teratogenicity:-

As with other cytotoxic agents Leukeran is potentially teratogenic.

Pregnancy:-

As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Leukeran. Partners should be informed of the drugs affect on germ cells.

This product should not be used in pregnancy, particularly in the first trimester, unless considered absolutely essential by the physician.

Lactation:-

Mothers receiving Leukeran should not breast-feed.

No data.

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) and very rare ( <1/10,000).

Neoplasms, benign, malignant and unspecified (incl cysts and polyps):

Common: Acute secondary haematologic malignancies (especially leukaemia and myelodysplastic syndrome), particularly after long term treatment.

Symptoms and signs:

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.

Pharmacotherapeutic Group: Alkylating agents, nitrogen mustard analogues

ATC Code: L01AA02

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 0.2 mg/kg bodyweight orally, the mean dose adjusted maximum plasma concentration (492 ± 160 ng/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 drug is well absorbed after oral dosage.

Metabolism:-

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.

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.

Effects on fertility:-

In rats, chlorambucil has been shown to damage spermatogenesis and cause testicular atrophy.

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.

Core:

Microcrystalline cellulose

Lactose, anhydrous

Colloidal anhydrous silica

Stearic acid

Coat:

Hypromellose

Titanium dioxide

Macrogol/ PEG 400

Synthetic red and yellow iron oxide

Not Applicable.

3 years

Store in a refrigerator at 2°C - 8°C. Store in the original container.

Leukeran tablets are supplied in amber (Type III) glass bottles with a child resistant polypropylene/ HDPE closure containing 25 or 50 tablets.

Not all pack sizes may be marketed

Safe handling of Leukeran tablets:-

The handling of Leukeran Tablets should follow guidelines for the handling of cytotoxic drugs according to prevailing local recommendations and/or regulations (for example, Royal Pharmaceutical Society of Great Britain Working Party on the Handling of Cytotoxic Drugs).

Provided the outer coating of the tablet is intact, there is no risk in handling Leukeran Tablets. Pregnant staff should not handle cytotoxic agents. Leukeran Tablets should not be divided.

Aspen Pharma Trading Limited

12/13 Exchange Place

I.F.S.C.

Dublin 1, Ireland

PA 1691/7/1

1^st April 1979/1^st April 2009

January 2011