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RX number of regimes have been used.

Chlorambucil has been used as an alternative to
CHLORAMBUCIL TABLETS nitrogen mustard with a reduction in toxicity but
similar therapeutic results.
2 MG
Paediatric population
1.NAME OF THE MEDICINAL Chlorambucil may be used in the management
PRODUCT of Hodgkin's disease in children. The dosage
regimes are similar to those used in adults.
Chlorambucil 2 mg tablets
NON-HODGKIN'S LYMPHOMA
2. QUALITATIVE AND
QUANTITATIVE COMPOSITION Adults

Each tablet contains 2 mg of the active Used as a single agent the usual dosage is 0.1-
ingredient chlorambucil. 0.2 mg/kg/day for 4-8 weeks initially,
maintenance therapy is then given either by a
Excipient(s) with known effect: reduced daily dosage or intermittent courses of
treatment.
Each tablet also contains 67.65 mg of lactose.
Chlorambucil is useful in the management of
For the full list of excipients, see section 6.1.
patients with advanced diffuse lymphocytic
3. PHARMACEUTICAL FORM lymphoma and those who have relapsed after
radiotherapy. There is no significant difference
Brown, round, biconvex, film-coated tablets. in the overall response rate obtained with
4. CLINICAL PARTICULARS chlorambucil as a single agent and combination
chemotherapy in patients with advanced non-
4.1 Therapeutic indications Hodgkin's lymphocytic lymphoma.
Chlorambucil is indicated in the treatment of
Paediatric population
Hodgkin's disease, certain forms of non-
Hodgkin's lymphoma, chronic lymphocytic Chlorambucil may be used in the management
leukaemia, and Waldenstrom's of non Hodgkin's disease in children. The
macroglobulinaemia. dosage regimes are similar to those used in
adults.
4.2 Posology and method of CHRONIC LYMPHOCYTIC LEUKAEMIA
administration Adults
The relevant literature should be consulted for Treatment with Chlorambucil is usually started
full details of the treatment schedules used. after the patient has developed symptoms or
Chlorambucil is an active cytotoxic agent for use when there is evidence of impaired bone marrow
only under the direction of physicians function (but not bone marrow failure) as
experienced in the administration of such agents. indicated by the peripheral blood count. Initially
Chlorambucil is given at a dosage of 0.15
Posology mg/kg/day until the total leucocyte count has
HODGKIN'S DISEASE fallen to 10,000 per µL. Treatment may be
resumed 4 weeks after the end of the first course
Adults and continued at a dosage of 0.1 mg/kg/day.
Used as a single agent in the palliative treatment In a proportion of patients, usually after about 2
of advanced disease a typical dosage is 0.2 years of treatment, the blood leucocyte count is
mg/kg/day for 4-8 weeks. Chlorambucil is reduced to the normal range, enlarged spleen
usually included in combination therapy and a and lymph nodes become impalpable and the
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proportion of lymphocytes in the bone marrow is While clinical experience has not revealed age-
reduced to less than 20%. related differences in response, drug dosage
generally should be titrated carefully in older
Patients with evidence of bone marrow failure patients, usually initiating therapy at the low end
should first be treated with prednisolone and of the dosage range.
evidence of marrow regeneration should be
obtained before commencing treatment with Method of administration
Chlorambucil. Intermittent high dose therapy
has been compared with daily Chlorambucil but Chlorambucil tablets are administered orally and
should be taken daily on an empty stomach (at
no significant difference in therapeutic response
least one hour before meals or three hours after
or frequency of side effects was observed
meals).
between the two treatment groups.
WALDENDSTROM'S 4.3 Contraindications
MACROGLOBULINAEMIA Hypersensitivity to chlorambucil or to any of the
excipients listed in section 6.1.
Adults
Chlorambucil is one of the treatment choices in 4.4 Special Warnings and precautions for
this indication. use
Continued treatment with chlorambucil should
Starting doses of 6-12 mg daily until leukopenia be assessed if a rash develops since there have
occurs are recommended followed by 2-8 mg been reports of Stevens-Johnson Syndrome in
daily indefinitely. patients receiving chlorambucil.
SPECIAL POPULATIONS Safe Handling of Chlorambucil tablets:
Renal impairment Immunisation using a live organism vaccine has
Dose adjustment is not considered necessary in the potential to cause infection in
renal impaired patients. immunocompromised hosts. Therefore,
immunisations with live organism vaccines are
Patients with evidence of impaired renal not recommended.
function should be carefully monitored as they
are prone to additional myelosuppression Patients who will potentially have autologous
associated with azotaemia. stem cell transplantation should not be treated
with chlorambucil long term.
Hepatic impairment
Monitoring
Patients with hepatic impairment should be
closely monitored for signs and symptoms of Since Chlorambucil is capable of producing
toxicity. irreversible bone marrow suppression, blood
counts should be closely monitored in patients
Since chlorambucil is primarily metabolized in under treatment.
the liver, dose reduction should be considered in
patients with severe hepatic impairment. At therapeutic dosage Chlorambucil depresses
However, there are insufficient data in patients lymphocytes and has less effect on neutrophil
with hepatic impairment to provide a specific and platelet counts and on haemoglobin levels.
dosing recommendation. Discontinuation of Chlorambucil is not
necessary at the first sign of a fall in neutrophils
Older people but it must be remembered that the fall may
continue for 10 days or more after the last dose.
No specific studies have been carried out in
older people, however, it may be advisable to Chlorambucil should not be given to patients
monitor renalor hepatic function and if there is who have recently undergone radiotherapy or
impairment then caution should be exercised. received other cytotoxic agents.
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When lymphocytic infiltration of the bone vivo; however, the clinical significance of this
marrow is present or the bone marrow is finding is unknown.
hypoplastic, the daily dose should not exceed 0.1
mg/kg body weight. 4.6 Fertility, pregnancy and lactation

Children with nephrotic syndrome, patients Pregnancy

prescribed high pulse dosing regimens and As with all cytotoxic therapy chemotherapy,
patients with a history of seizure disorder, adequate contraceptive precautions should be
should be closely monitored following advised when either partner is receiving
administration of Chlorambucil, as they may Chlorambucil.
have an increased risk of seizures.
The use of Chlorambucil should be avoided
Mutagenicity and Carcinogenicity whenever possible during pregnancy,
Chlorambucil has been shown to cause particularly during the first trimester. In any
chromatid or chromosome damage in man. individual case, the potential hazard to the foetus
must be balanced against the expected benefit to
Secondary malignancies, most commonly acute the mother.
secondary haematologic malignancies
(especially leukaemia and myelodysplastic Breast-feeding
syndrome) have been reported, particularly after Mothers receiving Chlorambucil should not
long term treatment. breast feed.
A comparison of patients with ovarian cancer Fertility:
who received alkylating agents with those who
did not, showed that the use of alkylating agents, Chlorambucil may cause suppression of ovarian
including Chlorambucil, significantly increased function and amenorrhoea has been reported
the incidence of acute leukaemia. following chlorambucil therapy.

Acute myelogenous leukaemia has been reported Azoospermia have been observed as a result of
in a small proportion of patients receiving therapy with chlorambucil although it is
Chlorambucil as long term adjuvant therapy for estimated that a total dose of at least 400 mg is
breast cancer. necessary.

The leukaemogenic risk must be balanced Varying degrees of recovery of spermatogenesis

against the potential therapeutic benefit when have been reported in patients with lymphoma
considering the use of Chlorambucil. following treatment with Chlorambucil in total
doses of 410-2600 mg.
Sugar intolerances
Teratogenicity
Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase As with other cytotoxic agents Chlorambucil is
deficiency or glucose-galactose malabsorption potentially teratogenic.
should not take this medication.
4.7 Effects on ability to drive and use
4.5 Interaction with other medicinal machines
products and other forms of interaction No information on the effects of Chlorambucil
Vaccinations with live organism vaccines are not on the ability to drive and use machines is
recommended in immunocompromised available.
individuals.
Purine nucleoside analogues (such as 4.8 Undesirable Effects
fludarabine, pentostatin and cladribine) For this product there is no modern clinical
increased the cytotoxicity of chlorambucil ex documentation which can be used as support for
determining the frequency of undesirable
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effects. Undesirable effects may vary in their Reproductive Not known Amenorrhoea, azoospermia.
incidence depending on the dose received and system and breast
disorders
also when given in combination with other General disorders Rare Pyrexia.
therapeutic agents. and administration
site conditions
The following convention has been utilised for
1. Although bone marrow suppression
the classification of frequency: Very common
frequently occurs, it is usually reversible if
(≥1/10), common (≥1/100 and <1/10),
Chlorambucil is withdrawn early enough.
uncommon (≥1/1000 and <1/100), rare
(≥1/10,000 and <1/1000) and very rare 2. Patients with a history of seizure disorder may
(<1/10,000) , not known (cannot be estimated be particularly susceptible.
from the available data).
3. Severe interstitial pulmonary fibrosis has
occasionally been reported in patients with
chronic lymphocytic leukaemia on long-term
Body System Side effects Chlorambucil therapy. However, this may be
Neoplasms benign, Common Acute secondary haematologic reversible on withdrawal of Chlorambucil.
malignant and malignancies (especially
unspecified leukaemia and myelodysplastic 4. Skin rash has been reported to progress to
(including cysts and syndrome), particularly after
polyps) long term treatment. serious conditions including Stevens-Johnson
Blood and Very common Leukopenia, neutropenia,
syndrome and toxic epidermal necrolysis.
lymphatic system thrombocytopenia, pancytopenia
disorders or bone marrow suppression1. Reporting of suspected adverse reactions
Common Anaemia. Reporting suspected adverse reactions after
Very rare Irreversible bone marrow failure. authorisation of the medicinal product is
Immune system Rare Hypersensitivity such as urticaria important. It allows continued monitoring of the
disorders and angioneurotic oedema
following initial or subsequent benefit/risk balance of the medicinal product.
dosing.
(See Skin and subcutaneous 4.9 Overdose
tissue disorders) Symptoms and signs
Nervous system Common Convulsions in children with
disorders nephrotic syndrome. Reversible pancytopenia was the main finding of
Rare Convulsions 2, partial and/or inadvertent overdoses of Chlorambucil.
generalised in children and
adults receiving therapeutic daily
Neurological toxicity ranging from agitated
doses or high pulse dosing behaviour and ataxia to multiple grand mal
regimens of chlorambucil. seizures has also occurred.
Very rare Movement disorders including
tremor, muscle twitching and Treatment
myoclonus in the absence of
convulsions. Peripheral As there is no known antidote the blood picture
neuropathy.
should be closely monitored and general
Respiratory, Very rare Interstitial pulmonary fibrosis3,
thoracic and interstitial pneumonia.
supportive measures should be instituted,
mediastinal together with appropriate blood transfusion if
disorders necessary.
Gastrointestinal Common Gastro-intestinal disorders such
disorders as nausea and vomiting,
diarrhoea and mouth ulceration.
Hepatobiliary Rare Hepatoxicity, jaundice. 5. PHARMACOLOGICAL
disorders
PROPERTIES
Skin and Uncommon Rash.
subcutaneous tissue Rare Stevens-Johnson syndrome, toxic 5.1 Pharmacodynamic properties
disorders epidermal necrolysis.4 (see
Immune system disorders)
Renal and urinary Very rare Sterile cystitis.
Pharmacotherapeutic group: Antineoplastic and
disorders immunomodulating agents, antineoplastic
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agents, alkylating agents, nitrogen mustard occurred between 0.25 and 2 hours after
analogues administration.
ATC code: L01AA02 Consistent with the rapid, predictable absorption
of chlorambucil, the inter-individual variability
Mechanism of action
in the plasma pharmacokinetics of chlorambucil
Chlorambucil is an aromatic nitrogen mustard has been shown to be relatively small following
derivative which acts as a bifunctional alkylating oral dosages of between 15 and 70 mg (2-fold
agent. intra-patient variability, and a 2-4 fold
interpatient variability in AUC).
In addition to interference with DNA replication,
chlorambucil induces cellular apoptosis via the The absorption of chlorambucil is reduced when
accumulation of cytosolic p53 and subsequent taken after food. In a study of ten patients, food
activation of an apoptosis promoter (Bax). intake increased the median time to reach
Cmax by greater than 100%, reduced the peak
Pharmacodynamic effects plasma concentration by greater than 50% and
The cytotoxic effect of chlorambucil is due to reduced mean AUC (0-∞) by approximately
both chlorambucil and its major metabolite 27% (see section 4.2).
phenylacetic acid mustard (see section 5.2). Distribution
Mechanism of resistance Chlorambucil has a volume of distribution of
Chlorambucil is an aromatic nitrogen mustard approximately 0.14-0.24 L/kg. Chlorambucil
derivative and resistance to nitrogen mustards covalently binds to plasma proteins, primarily to
has been reported to be secondary to: alterations albumin (98%), and covalently binds to red
in the transport of these agents and their blood cells.
metabolites via various multi-resistant proteins, Biotransformation
alterations in the kinetics of the DNA cross-links
formed by these agents and changes in apoptosis Chlorambucil is extensively metabolised in the
and altered DNA repair activity. Chlorambucil is liver by monodichloroethylation and β-
not a substrate of multi-resistant protein 1 oxidation, forming phenylacetic acid mustard
(MRP1 or ABCC1), but its glutathione (PAAM) as the major metabolite, which
conjugates are substrates of MRP1 (ABCC1) possesses alkylating activity in animals.
and MRP2 (ABCC2). Chlorambucil and PAAM degrade in
vivo forming monohydroxy and dihydroxy
derivatives. In addition, chlorambucil reacts with
5.2 Pharmacokinetic properties glutathione to form mono- and diglutathionyl
conjugates of chlorambucil.
Absorption
Following the administration of approximately
Chlorambucil is well absorbed by passive 0.2 mg/kg of oral chlorambucil, PAAM was
diffusion from the gastrointestinal tract and is detected in the plasma of some patients as early
measurable within 15-30 minutes of as 15 minutes and mean dose adjusted plasma
administration. The bioavailability of oral concentration (Cmax) of 306 ± 73 nanograms/ml
chlorambucil is approximately 70% to 100% occurred within 1 to 3 hours.
following administration of single doses of 10-
200 mg. Elimination

In a study of 12 patients administered The terminal phase elimination half-life ranges

approximately 0.2 mg/kg of oral chlorambucil, from 1.3-1.5 hours for chlorambucil and is
the mean dose adjusted maximum plasma approximately 1.8 hours for PAAM. The extent
concentration (492 ± 160 nanograms/ml) 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
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the urine in 24 hours, with the rest of the dose Colloidal anhydrous silica
eliminated mainly as monohydroxy and
dihydroxy derivatives. Stearic acid (E570)
Tablet Film Coating
5.3 Preclinical safety data
Hypromellose
Mutagenicity and Carcinogenicity
Titanium dioxide (E171)
As with other cytotoxic agents chlorambucil is
mutagenic in in vitro and in vivo genotoxicity Synthetic yellow iron oxide (E172)
tests and carcinogenic in animals and humans.
Synthetic red iron oxide (E172)
Reproductive toxicology
Macrogol
In rats, chlorambucil has been shown to damage
spermatogenesis and cause testicular atrophy. 6.2 Incompatibilities
None known.
Teratogenicity
Chlorambucil has been shown to induce 6.3 Shelf life
developmental abnormalities, such as short or 3 years.
kinky tail, microcephaly and exencephaly,
digital abnormalities including ectro-, brachy-, 6.4 Special precautions for storage
syn- and polydactyly and long-bone Store in a refrigerator (2°C-8°C)
abnormalities such as reduction in length,
absence of one or more components, total 6.5 Nature and contents of container
absence of ossification sites in the embryo of Chlorambucil tablets are brown, round,
mice and rats following a single oral biconvex, film-coated tablets, one side engraved
administration of 4 to 20 mg/kg. with 'L' and the other side engraved 'GX EG3',
supplied in amber glass bottles with a child
Chlorambucil has also been shown to induce resistant closure containing 25 tablets..
renal abnormalities in the offspring of rats
following a single intraperitoneal injection of 3 6.6 Special precautions for disposal and
to 6 mg/kg. other handling
Chlorambucil is an active cytotoxic agent for use
Brain and plasma pharmacokinetics only under the direction of physicians
After oral administration of 14C-marked experienced in the administration of such agents.
chlorambucil to rats, the highest concentrations The handling of Chlorambucil Tablets should
of radioactive marked material were found in the follow guidelines for the handling of cytotoxic
plasma, in the liver and in the kidneys. Only drugs according to prevailing local
small concentrations were measured in the recommendations and/or regulations (for
cerebral tissue of rats after intravenous example, Royal Pharmaceutical Society of Great
administration of chlorambucil. Britain Working Party on the Handling of
6. PHARMACEUTICAL Cytotoxic Drugs).
PARTICULARS Provided that the outer coating of the tablet is
intact, there is no risk in handling Chlorambucil
6.1 List of excipients Tablets.
Chlorambucil Tablets should not be divided.
Tablet Core
Microcrystalline cellulose (E460)
Anhydrous lactose
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7. MANUFACTURER:

Manufactured in India by:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Survey No.188/1 to 189/1,190/1 to 4,
Athiyawad, Dabhel,
Daman- 396210 (INDIA)