4.1. Therapeutic indications

Chlorambucil 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

The relevant literature should be consulted for full details of the treatment schedules used.Chlorambucil is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents. Posology

HODGKIN'S DISEASE

Adults

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. 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 population

Chlorambucil may be used in the management of Hodgkin's disease in children. The dosage regimes are similar to those used in adults. NON-HODGKIN'S LYMPHOMA

Adults

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.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 population

Chlorambucil 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

Adults

Treatment 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 Adults

Chlorambucil 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. SPECIAL POPULATIONS

Renal impairment

Dose 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 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, 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 administration

Chlorambucil tablets are administered orally and should be taken daily on an empty stomach (at least one hour before meals or three hours after meals).

4.3. Contraindications

Hypersensitivity to chlorambucil or to any of the excipients listed in section 6.1.

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).Safe Handling of Chlorambucil tablets: See section 6.6.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 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 Carcinogenicity

Chlorambucil 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 intolerances

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

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).Purine nucleoside analogues (such as fludarabine, pentostatin and cladribine) increased the cytotoxicity of chlorambucil ex vivo; however, the clinical significance of this finding is unknown.

4.6. Fertility, pregnancy and lactation

Pregnancy

As 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-feeding

Mothers 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. Teratogenicity

As with other cytotoxic agents Chlorambucil is potentially teratogenic.

4.7. Effects on ability to drive and use machines

No information on the effects of Chlorambucil on the ability to drive and use machines is available.

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 (≥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) , not known (cannot be estimated from the available data). 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.

Common Anaemia.

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.

1. Although bone marrow suppression frequently occurs, it is usually reversible if Chlorambucil is withdrawn early enough. 2. Patients with a history of seizure disorder may be particularly susceptible.3. Severe interstitial pulmonary fibrosis has occasionally been reported in patients with chronic lymphocytic leukaemia on long-term Chlorambucil therapy. However, this may be reversible on withdrawal of Chlorambucil.4. Skin rash has been reported to progress to serious conditions including Stevens-Johnson syndrome and toxic epidermal necrolysis. Reporting of suspected adverse reactions

Reporting 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.

4.9. Overdose

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. Treatment

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.