Summary of Product Characteristics Updated 03-Nov-2015 | Aspen
AdultsUsed as a single agent in the palliative treatment of advanced disease a typical dosage is 0.2 mg/kg/day for 4-8 weeks. Chlorambucil is usually included in combination therapy and a number of regimes have been used. Chlorambucil has been used as an alternative to nitrogen mustard with a reduction in toxicity but similar therapeutic results.
Paediatric populationChlorambucil may be used in the management of Hodgkin's disease in children. The dosage regimes are similar to those used in adults.
AdultsUsed 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.Chlorambucil 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.
Paediatric populationChlorambucil may be used in the management of non Hodgkin's disease in children. The dosage regimes are similar to those used in adults.
CHRONIC LYMPHOCYTIC LEUKAEMIA
AdultsTreatment with Chlorambucil 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 Chlorambucil 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%. 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 Chlorambucil. Intermittent high dose therapy has been compared with daily Chlorambucil but no significant difference in therapeutic response or frequency of side effects was observed between the two treatment groups.WALDENDSTROM'S MACROGLOBULINAEMIA
AdultsChlorambucil is one of the treatment choices in this indication.Starting doses of 6-12 mg daily until leukopenia occurs are recommended followed by 2-8 mg daily indefinitely.
Renal impairmentDose adjustment is not considered necessary in renal impaired patients.Patients with evidence of impaired renal function should be carefully monitored as they are prone to additional myelosuppression associated with azotaemia.
Hepatic impairmentPatients 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 peopleNo specific studies have been carried out in older people, however, it may be advisable to monitor renalor hepatic function and if there is impairment then caution should be exercised. While clinical experience has not revealed age-related differences in response, drug dosage generally should be titrated carefully in older patients, usually initiating therapy at the low end of the dosage range.
Method of administrationChlorambucil tablets are administered orally and should be taken daily on an empty stomach (at least one hour before meals or three hours after meals).
MonitoringSince Chlorambucil is capable of producing irreversible bone marrow suppression, blood counts should be closely monitored in patients under treatment.At therapeutic dosage Chlorambucil depresses lymphocytes and has less effect on neutrophil and platelet counts and on haemoglobin levels. Discontinuation of Chlorambucil 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.Chlorambucil 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 Chlorambucil, as they may have an increased risk of seizures.
Mutagenicity and CarcinogenicityChlorambucil 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 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.
Sugar intolerancesPatients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.
PregnancyAs with all cytotoxic therapy chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Chlorambucil.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.
Breast-feedingMothers receiving Chlorambucil should not breast feed. Fertility: Chlorambucil may cause suppression of ovarian function and amenorrhoea has been reported following chlorambucil therapy.Azoospermia have 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 410-2600 mg.
TeratogenicityAs with other cytotoxic agents Chlorambucil is potentially teratogenic.
|Body System||Side effects|
|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||Leukopenia, neutropenia, thrombocytopenia, pancytopenia or bone marrow suppression1.|
|Very rare||Irreversible bone marrow failure.|
|Immune system disorders||Rare||Hypersensitivity such as urticaria and angioneurotic oedema following initial or subsequent dosing. (See Skin and subcutaneous tissue disorders)|
|Nervous system disorders||Common||Convulsions in children with nephrotic syndrome.|
|Rare||Convulsions 2, partial and/or generalised in children and adults receiving therapeutic daily doses or high pulse dosing regimens of chlorambucil.|
|Very rare||Movement disorders including tremor, muscle twitching and myoclonus in the absence of convulsions. Peripheral neuropathy.|
|Respiratory, thoracic and mediastinal disorders||Very rare||Interstitial pulmonary fibrosis3, interstitial pneumonia.|
|Gastrointestinal disorders||Common||Gastro-intestinal disorders such as nausea and vomiting, diarrhoea and mouth ulceration.|
|Hepatobiliary disorders||Rare||Hepatoxicity, jaundice.|
|Skin and subcutaneous tissue disorders||Uncommon||Rash.|
|Rare||Stevens-Johnson syndrome, toxic epidermal necrolysis.4 (see Immune system disorders)|
|Renal and urinary disorders||Very rare||Sterile cystitis.|
|Reproductive system and breast disorders||Not known||Amenorrhoea, azoospermia.|
|General disorders and administration site conditions||Rare||Pyrexia.|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
Symptoms and signsReversible 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.
TreatmentAs 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.
Mechanism of actionChlorambucil is an aromatic nitrogen mustard derivative which acts as a bifunctional alkylating agent. In addition to interference with DNA replication, chlorambucil induces cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of an apoptosis promoter (Bax).
Pharmacodynamic effectsThe cytotoxic effect of chlorambucil is due to both chlorambucil and its major metabolite phenylacetic acid mustard (see section 5.2).
Mechanism of resistanceChlorambucil is an aromatic nitrogen mustard derivative and resistance to nitrogen mustards has been reported to be secondary to: alterations in the transport of these agents and their metabolites via various multi-resistant proteins, alterations in the kinetics of the DNA cross-links formed by these agents and changes in apoptosis and altered DNA repair activity. Chlorambucil is not a substrate of multi-resistant protein 1 (MRP1 or ABCC1), but its glutathione conjugates are substrates of MRP1 (ABCC1) and MRP2 (ABCC2).
AbsorptionChlorambucil is well absorbed by passive diffusion from the gastrointestinal tract and is measurable within 15-30 minutes of administration. The bioavailability of oral chlorambucil is approximately 70% to 100% following administration of single doses of 10-200 mg.In a study of 12 patients administered approximately 0.2 mg/kg of oral chlorambucil, the mean dose adjusted maximum plasma concentration (492 ± 160 nanograms/ml) occurred between 0.25 and 2 hours after administration.Consistent with the rapid, predictable absorption of chlorambucil, the inter-individual variability in the plasma pharmacokinetics of chlorambucil has been shown to be relatively small following oral dosages of between 15 and 70 mg (2-fold intra-patient variability, and a 2-4 fold interpatient variability in AUC). The absorption of chlorambucil is reduced when taken after food. In a study of ten patients, food intake increased the median time to reach Cmax by greater than 100%, reduced the peak plasma concentration by greater than 50% and reduced mean AUC (0-∞) by approximately 27% (see section 4.2).
DistributionChlorambucil has a volume of distribution of approximately 0.14-0.24 L/kg. Chlorambucil covalently binds to plasma proteins, primarily to albumin (98%), and covalently binds to red blood cells.
BiotransformationChlorambucil is extensively metabolised in the liver by monodichloroethylation and β-oxidation, forming phenylacetic acid mustard (PAAM) as the major metabolite, which possesses alkylating activity in animals. Chlorambucil and PAAM degrade in vivo forming monohydroxy and dihydroxy derivatives. In addition, chlorambucil reacts with glutathione to form mono- and diglutathionyl conjugates of chlorambucil.Following the administration of approximately 0.2 mg/kg of oral chlorambucil, PAAM was detected in the plasma of some patients as early as 15 minutes and mean dose adjusted plasma concentration (Cmax) of 306 ± 73 nanograms/ml occurred within 1 to 3 hours.
EliminationThe terminal phase elimination half-life ranges from 1.3-1.5 hours for chlorambucil and is approximately 1.8 hours for PAAM. The extent of renal excretion of unchanged chlorambucil or PAAM is very low; less than 1% of the administered dose of each of these is excreted in the urine in 24 hours, with the rest of the dose eliminated mainly as monohydroxy and dihydroxy derivatives.
Mutagenicity and CarcinogenicityAs with other cytotoxic agents chlorambucil is mutagenic in in vitro and in vivo genotoxicity tests and carcinogenic in animals and humans.
Reproductive toxicologyIn rats, chlorambucil has been shown to damage spermatogenesis and cause testicular atrophy.
TeratogenicityChlorambucil 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 to 20 mg/kg.Chlorambucil has also been shown to induce renal abnormalities in the offspring of rats following a single intraperitoneal injection of 3 to 6 mg/kg.
Brain and plasma pharmacokineticsAfter oral administration of 14C-marked chlorambucil to rats, the highest concentrations of radioactive marked material were found in the plasma, in the liver and in the kidneys. Only small concentrations were measured in the cerebral tissue of rats after intravenous administration of chlorambucil.
Tablet CoreMicrocrystalline cellulose (E460)Anhydrous lactoseColloidal anhydrous silicaStearic acid (E570)
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