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5.3      Preclinical safety data

 

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.

 

 

 

10.      DATE OF REVISION OF THE TEXT

 

January 2018 February 2016

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2.        QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each tablet contains 2 mg of the active ingredient chlorambucil.

 

Excipient(s) with known effect:

 

4.2      Posology and method of administration

 

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

 

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.

 

Posology

Waldenstrom's macroglobulinaemia

 

Leukeran 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

 

Chlorambucil has an extremely low urinary excretion and hence renal excretion is not considered an important pathway in chlorambucil elimination. Dose adjustment is not considered necessary in renally impaired patients. However no formal studies of the effects of renal insufficiency on the pharmacokinetics of chlorambucil have been carried out.

 

Paediatric population

 

Leukeran may be used in the management of Hodgkin's disease and non‑Hodgkin's lymphomas in

the paediatric population. 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 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 elderly patients, usually initiating therapy at the low end of the dosage range.

 

Method of administration

 

4.3      Contraindications

 

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

 

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

 

4.4      Special warnings and precautions for use

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised individuals. 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.

 

Safe handling of Leukeran Tablets

See section 6.6.

 

 

The paediatric population 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.

 

4.5 Interaction with other medicinal products and other forms of interaction

 

 

4.6      Fertility, pregnancy and lactation

 

Breast‑feeding

Mothers receiving Leukeran should not breast-feed.

 

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 (see section 5.3).

 

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.

 

The following convention has been utilised for the classification of frequency: Very common (³1/10), common (³1/100 and <1/10), uncommon (³1/1000 and <1/100), rare (³1/10,000 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.
Nervous system disorders	Common	Convulsions in the paediatric population with nephrotic syndrome.
	Rare	Convulsions 2, partial and/or generalised in the paediatric population 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 necrolysis4.
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 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:

 

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

 

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

 

 

5.        PHARMACOLOGICAL PROPERTIES

 

5.1      Pharmacodynamic properties

 

Pharmacotherapeutic Group: Antineoplastic and immunomodulating agents, antineoplastic agents, alkylating agents, nitrogen mustard analogues, ATC Code: L01AA02.

 

Pharmacodynamic effects

 

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

 

 

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).

 

Biotransformation

 

5.3      Preclinical safety data

 

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.

 

10.      DATE OF REVISION OF THE TEXT

 

February 2016 April 2014

 

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7 MARKETING AUTHORISATION HOLDER

12/13 Exchange Place

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Citywest Business Campus

Dublin 24

10 DATE OF REVISION OF THE TEXT

February April 20143

The following text highlighted in bold has been added in section 4.2  Posology and Method of Administration

Leukeran is taken orally. High gastric pH has been shown to significantly decrease the bioavailability of Leukeran therefore ingestion on an empty stomach (one hour before a meal or 3 hours after) is advised.

Renal impairment:-

Chlorambucil has an extremely low urinary excretion and hence renal excretion is not considered an important pathway in chlorambucil elimination. However no formal studies of the effects of renal insufficiency on the pharmacokinetics of chlorambucil have been carried out.

Dose adjustment is not considered necessary in renally impaired patients.

 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.

4.4 Special Warnings and Special Precautions for Use
Monitoring

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

4.5     Interactions with Other Medicaments and Other Forms of Interaction

Purine nucleoside analogues (such as fludarabine, pentostatin and cladribine) increased the cytotoxicity of chlorambucil in vitro. However, the clinical significance of this finding is unknown. Clinically the combination of purine nucleoside analogues and alkylating agents have been shown to produce high disease response rates however the combinations have also resulted in higher rates of haematological toxicities.

5. Pharmacological Properties

5.1.       Pharmacodynamic Properties

Pharmacotherapeutic Group:  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 Pharmacokinetics; Metabolism).

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).

1.2.       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.

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 Dosage & Administration).

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.

Metabolism:-

Chlorambucil 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 (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.

 

 

Improved electronic presentation

Improved electronic presentation

Product ownership transfered from GSK to Aspen

 2        qualitative and QUantitative composition

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.

 

3   pharmaceutical form

Film-coated tablet (Tablet)

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

………………………

4.3     Contraindications

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

Hypersensitivity to chlorambucil or to any of the excipients.

……………………………

6.5.    Nature and Contents of 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

6.6.    Instructions for Use/Handling Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

Blood and Lymphatic system disorders:

Very common: leucopenia, neutropenia, thrombocytopenia, panyctopenia

Common: anaemia