SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Chlorambucil 2 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2 mg of the active ingredient chlorambucil.

Excipient(s) with known effect:

Each tablet also contains 67.65 mg of lactose.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Brown, round, biconvex, film-coated tablets, one side engraved with “L” and the other side engraved ‘GX EG 3’

4    CLINICAL PARTICULARS

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 pL. 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

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 patients, however, it may be advisable to monitor renal or 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    Interactions 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.

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

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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic agents, alkylating agents, nitrogen mustard analogues, ATC code: L01AA02.

Mechanism of action

Chlorambucil 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 effects

The cytotoxic effect of chlorambucil is due to both chlorambucil and its major metabolite phenylacetic acid mustard (see section 5.2).

Mechanism of resistance

Chlorambucil 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).

5.2 Pharmacokinetic properties

Absorption

Chlorambucil 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 C_max 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).

Distribution

Chlorambucil 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.

Biotransformation

Chlorambucil is extensively metabolised in the liver by monodichloroethylation and P-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 (C_max) of 306    73 nanograms/ml occurred within 1 to 3 hours.

Elimination

The 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.

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.

Reproductive toxicology

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 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 pharmacokinetics

After 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.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet Core

Microcrystalline cellulose (E460) Anhydrous lactose Colloidal anhydrous silica Stearic acid (E570)

Tablet Film Coating

Hypromellose Titanium dioxide (E171)

Synthetic yellow iron oxide (E172) Synthetic red iron oxide (E172) Macrogol

6.2 Incompatibilities

None known.

6.3 Shelf life

3 years.

6.4    Special precautions for storage

Store in a refrigerator (2 °C - 8 °C)

6.5    Nature and contents of container

Chlorambucil tablets are brown, round, biconvex, film-coated tablets, one side engraved with 'L' and

the other side engraved 'GX EG3', supplied in amber glass bottles with a child resistant closure

containing 25 tablets.

6.6 Special precautions for disposal and other Handling

Chlorambucil is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.

Safe handling of Chlorambucil Tablets: The handling of Chlorambucil 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 Chlorambucil Tablets. Chlorambucil Tablets should not be divided.

7. MARKETING AUTHORISATION HOLDER

Aspen Pharma Trading Limited 3016 Lake Drive Citywest Business Campus Dublin 24 Ireland

8 MARKETING AUTHORISATION NUMBER(S)

PL 39699/0041

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22 June 2006

10 DATE OF REVISION OF THE TEXT

28/10/2015