1. Name Of The Medicinal Product
Leukeran® Tablets 2 mg
2. Qualitative And Quantitative Composition
Each tablet contains 2 mg of the active ingredient chlorambucil.
3. Pharmaceutical Form
Film-coated tablet
4. Clinical Particulars
4.1 Therapeutic Indications
Leukeran is indicated in the treatment of Hodgkin's disease, certain forms of non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, and Waldenstrom's macroglobulinaemia.
4.2 Posology And Method Of Administration
Adults: 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 bone 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 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 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 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 Macroglobulinaemia: 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 regimes 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.
4.3 Contraindications
Hypersensitivity to chlorambucil or to any of the excipients.
4.4 Special Warnings And Precautions For Use
Continued treatment with chlorambucil should be assessed if a rash develops since there have been reports of Stevens-Johnson Syndrome in patients receiving chlorambucil (see section 4.8).
Leukeran is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.
Safe Handling of Leukeran tablets:
See 6.6 Instructions for Use/Handling
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.
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 body weight.
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.
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:
Leukeran has been shown to cause chromatid or chromosome damage in man.
Secondary malignancies, most commonly acute secondary haematologic malignancies (especially leukaemia and myelodysplastic syndrome) have been reported, particularly after long term treatment (see Section 4.8).
A comparison of patients with ovarian cancer who received alkylating agents with those who did not, showed that the use of alkylating agents, including Leukeran, significantly increased the incidence of acute leukaemia.
Acute myelogenous leukaemia has been reported in a small proportion of patients receiving Leukeran as long term adjuvant therapy for breast cancer.
The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of Leukeran.
Sugar intolerances:
Patients with rare hereditary problems of glucose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication. Each Leukeran 2mg tablet contains 68mg of lactose.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4 Special Warnings and Precautions for use).
Patients receiving phenylbutazone may require a reduced dose of Leukeran.
4.6 Pregnancy And Lactation
As with other cytotoxic agents Leukeran is potentially teratogenic. The use of Leukeran 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 breast feed.
4.7 Effects On Ability To Drive And Use Machines
None known
4.8 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 (
Neoplasms, benign, malignant, and unspecified (including cysts and polyps) | |
Common: | Acute secondary haematologic malignancies (especially leukaemia and myelodysplastic syndrome), particularly after long term treatment. |
Blood and lymphatic system disorders | |
Very common: | Leucopenia, neutropenia, thrombocytopenia, pancytopenia or bone marrow suppression. |
Common: | Anaemia. |
Very rare: | Irreversible bone marrow failure. |
Although bone marrow suppression frequently occurs, it is usually reversible if Leukeran is withdrawn early enough. | |
Immune system disorders | |
Uncommon: | Rash. |
Rare: | Allergic reactions such as urticaria and angioneurotic oedema following initial or subsequent dosing. Stevens-Johnson syndrome and toxic epidermal necrolysis.
|
On rare occasions skin rash has been reported to progress to serious conditions including Stevens-Johnson Syndrome and toxic epidermal necrolysis.
Nervous system disorders | |
Common: | Seizures in children with nephrotic syndrome. |
Rare: | Seizures#, focal and/or generalised in children and adults receiving therapeutic daily doses or high pulse dosing regimens of chlorambucil. |
Very rare: | Movement disorders including tremor, twitching and myoclonia in the absence of convulsions. Peripheral neuropathy.
|
Respiratory, thoracic and mediastinal disorders | |
Very rare: | Interstitial pulmonary fibrosis, interstitial pneumonia. |
Severe interstitial pulmonary fibrosis has occasionally been reported in patients with chronic lymphocytic leukaemia on long-term Leukeran therapy. However, this may be reversible on withdrawal of Leukeran.
Gastrointestinal disorders | |
Common: | Gastro-intestinal disturbances such as nausea and vomiting, diarrhoea and oral ulceration. |
Hepatobiliary disorders | |
Rare: | Hepatoxicity, jaundice. |
Skin and subcutaneous tissue disorders | |
Uncommon: | Rash. |
Rare: | Allergic reactions such as urticaria and angioneurotic oedema following initial or subsequent dosing. Stevens-Johnson syndrome and toxic epidermal necrolysis.
|
Renal and urinary disorders | |
Very rare: | Sterile cystitis. |
General disorders and administration site conditions | |
Rare: | Drug fever. |
4.9 Overdose
Reversible pancytopenia was the main finding of inadvertent overdoses of Leukeran. 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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.
5.2 Pharmacokinetic Properties
In a study of 12 patients administered chlorambucil 0.2 mg/kg body weight 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]-chlorambucil indicates that the drug 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 body weight 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.
5.3 Preclinical Safety Data
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.
Teratogenicity
See information under 'Pregnancy and Lactation' section.
Chlorambucil has been shown to induce skeletal abnormalities in the embryos 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.
Effects on fertility
Leukeran may cause suppression of ovarian function and amenorrhoea has been reported following Leukeran therapy.
Azoospermia has been observed as a result of therapy with Leukeran 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 Leukeran in total doses of 400-2600 mg.
In rats, chlorambucil has been shown to damage spermatogenesis and cause testicular atrophy.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Tablet Core:
Microcrystalline cellulose
Anhydrous lactose
Colloidal anhydrous silica
Stearic acid
Tablet Film Coating:
Hypromellose
Titanium dioxide
Synthetic yellow iron oxide
Synthetic red iron oxide
Macrogol
6.2 Incompatibilities
None known.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Store at 2°C - 8°C.
6.5 Nature And Contents Of Container
Leukeran are brown film-coated, round, biconvex tablets engraved “GX EG3” on one side and “L” on the other, supplied in amber glass bottles with a child resistant closure containing 25 tablets.
6.6 Special Precautions For Disposal And Other Handling
Leukeran is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.
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 that the outer coating of the tablet is intact, there is no risk in handling Leukeran Tablets. Leukeran Tablets should not be divided.
Administrative Data
7. Marketing Authorisation Holder
ALKOPHARMA SARL
45-47, rte d'Arlon
L – 1140 Luxembourg
8. Marketing Authorisation Number(S)
PL 36637/0007
9. Date Of First Authorisation/Renewal Of The Authorisation
22.06.2006
10. Date Of Revision Of The Text
September 2010
11. LEGAL STATUS
POM
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