Chlorambucil

CHLORAMBUCIL

Complete information including dosage, side effects, interactions and pregnancy & breast feeding warnings for patient and professional use.

Overview and uses

Chlorambucil is a very slow acting alkylating agent used for the treatment of cancer.

Indication (uses)

For the treatment of:

  • Chronic lymphatic leukemia
  • Malignant lymphomas including Lymphosarcoma, giant follicular lymphoma and Hodgkin’s disease

Though it is not curative in any of these disorders, it may produce clinically useful palliation.

Pharmacological classification

Alkylating agent used for the treatment of cancer.

Brand names

LEUKERAN®

Dosage form

  • Supplied as brown, film coated, round, biconvex tablets.
  • Available in strength of 2 mg Chlorambucil.
  • Supplied in amber coloured glass bottles with child resistant closures.
  • One side of the tablet is engraved with ‘GXEG3’ and other side of the tablet is engraved with an ‘L’.

Mechanism of action:

Alkylating agents produce highly reactive carbonium ion intermediates which transfer alkyl groups to cellular macromolecules by forming covalent bonds. These intermediates may react with carboxyl, hydroxyl, amino, sulfhydryl and phosphate groups of biomacromolecules. Alkylation results in cross linking/abnormal base pairing/scission of DNA strand. Cross linking of nucleic acids with proteins can also take place.

Chlorambucil interferes with DNA replication and induces cellular apoptosis via accumulation of cytosolic p53 and subsequent activation of Bax, an apoptosis promoter.

Dosage

  • 1 mg to 0.2 mg per kg of the body weight per day for 3 to 6 weeks as required.
  • This usually amounts to 4 to 10 mg per day for the average patient.
  • The entire daily dose can be given at one time.
  • Patient should be closely monitored for the reduction in white blood cell count and dose should be reduced accordingly.
  • Patients with Hodgkin’s disease usually require 0.2 mg/kg of the body weight daily.
  • Patients with other lymphomas or chronic lymphocytic leukemia usually require 0.1 mg/kg of the body weight daily.
  • Dose should not exceed 0.1 mg/kg of the body weight if lymphocytic infiltration of the bone marrow is present or if the bone marrow is hypoplastic.

Renal dose adjustments

  • Renal elimination of Chlorambucil and its metabolites is less than 1% of the administered dose.
  • Hence, renal impairment is not expected to significantly impact the elimination of Chlorambucil.
  • The effect of renal impairment of Chlorambucil elimination has not been formally studied.

Hepatic dose adjustments

  • Specific dosing recommendation for the patients with hepatic impairment is not available due to insufficient data.
  • Chlorambucil is primarily metabolized by liver.
  • Patients with hepatic impairment should be closely monitored for toxicity.

Geriatric dose adjustments

  • Data not available.
  • Caution should be exercised while administering Chlorambucil in elderly patients since an increase in age is related to reduced hepatic, renal and/or cardiac functions as well as presence of concomitant disease or treatment of concomitant disease.

Pediatric use

  • Safety and efficacy of Chlorambucil in pediatric patients has not been established.

Overdosage

  • No specific antidote is known.
  • Chlorambucil is not dialyzable.
  • Symptoms of Overdosage includes
  • Neurological toxicity ranging from agitated behavior and ataxia to multiple grand mal seizures.
  • Reversible pancytopenia
  • Treatment of overdosage involves
  • General supportive measures.
  • Appropriate blood transfusion.
  • Close monitoring of blood and blood components.

Side effects or adverse effects

  • Hypersensitivity reactions
    • Anaphylaxis has been reported with Chlorambucil use.
    • Pain in chest or abdomen, skin rash, difficulty in breathing, rapid breathing, shortness of breath, dizziness, fainting, low blood pressure are some of the symptoms.
    • Consult your doctor as soon as possible.
  • Other systemic side effects
    • Jaundice
    • Vertigo
    • Tinnitus
    • Diminished hearing
    • Occurrence/precipitation of hemolytic anemia
  • Bone marrow depression
    • Bone marrow depression is the most serious side effect/toxicity. It is also a limiting factor for the dose. Infections and bleeding are the common complications.
    • Bone marrow depression results in granulocytopenia, agranulocytosis, thrombocytopenia and aplastic anemia.
    • Consult your doctor as soon as possible if you observe any of the below mentioned symptoms:
      • Sore throat
      • Chills
      • Sudden fever
      • Weakness in limbs
      • Mouth ulcers
      • Bleeding gums
      • Sore mouth
      • Fast heart rate
      • Low blood pressure
      • Sore gums
      • Skin abscesses
      • Rapid breathing
      • Rapid progression of infection of any organ
      • Rapid progression of Septicemia
    • Gastrointestinal side effects
      • Nausea and vomiting are commonly observed with anti-cancer medicines.
      • Mucositis – painful inflammation and ulceration of mucus membrane lining the digestive tract.
      • Diarrhea, shredding of mucosa and haemorrhage due to decreased rate of renewal of gastrointestinal mucosa lining.
    • Skin
      • Alopecia or hair loss.
      • Dermatitis
    • Oral side effects
      • Breaches during chewing.
      • Depression of immunity due to reduction in number of WBCs largely increases the risk of oral infections.
      • Bleeding gums
      • Rapid progression of dental caries.
    • Gonadal side effects
      • Infertility due to Oligozoospermia in males.
      • Impotence in males.
      • Loss or reduces sex drive.
      • Inhibition of ovulation in females
      • Amenorrhea in females.
      • Damage to germinal cells may lead to mutagenesis.
    • Lymphoreticular tissue
      • Lymphocytopenia (reduced number of lymphocytes)
      • Inhibition of lymphocyte function.
      • Suppression of immunity due to bone marrow depression and reduced lymphocyte function highly increases the risk of opportunistic infections like:
        • Candida and other infections causing deep mycosis.
        • Cytomegalo virus
        • Herpes zoster
        • Pneumocystis jiroveci
        • Toxoplasma
      • Fetal side effects
        • Use of anti-cancer medicines in pregnant women may cause fetal damage leading to:
          • Fetal death
          • Abortion
          • Teratogenesis
        • Renal side effects
          • Renal failure, Gout and Urate stones may develop in urinary tract.
        • Hyperuricemia
          • An elevated level of uric acid is common in leukemia and bulky lymphomas.
  • Please note: The side effects mentioned above are from the reported cases. However, side effects are not limited to above mentioned conditions and symptoms. Consult your doctor as soon as possible if you feel or observe any symptoms that you relate to your treatment.

Warnings & Precautions

  • Chlorambucil should not be used in patients whose disease has demonstrated a prior resistance to the drug.
  • Contra-indicated in patients with known hypersensitivity to Chlorambucil.
  • Chlorambucil should not be given to patients with conditions other than chronic lymphatic leukemia or malignant lymphomas.
  • Chlorambucil has shown to cause chromosome or chromatid damage in humans. Both reversible and permanent sterility has been reported in both sexes receiving Chlorambucil.
  • Chlorambucil can cause fetal damage when administered to a pregnant woman.

Pregnancy & breast feeding warnings

  • Pregnancy
  • Category D, which means there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
  • Nursing:
  • It is not known whether Chlorambucil is excreted in human breast milk or not.
  • Since many drugs are excreted in milk and because of the potential for side effects in nursing infants, a decision should be made whether to discontinue drug or to discontinue nursing.

Interactions

Drug – drug interactions

  • Concomitant use of Chlorambucil with following drugs/medicines should be strictly avoided.
    • Leflunomide as it increases the risk of infections.
    • Adalimumab as it increases the risk of infections.
    • Teriflunomide as it increases the risk of infections.
    • Certolizumab as it increases the risk of infections.
    • Clozapine as it may lower the WBC count.
    • Deferiprone as it may lower the WBC count.
    • Etanercept as it increases the risk of infections.
    • Fingolimod as it increases the risk of infections.
    • Golimumab as it increases the risk of infections.
    • Infliximab as it increases the risk of infections.
    • Talimogene as it increases the risk of herpes infections.
    • Nalidixic acid as the combination may cause unusual bruising or bleeding, nausea, stomach pain, unusual weakness, low fever and loss of appetite.
    • Natalizumab as it increases the risk of infections.
    • Tofacitinib as it increases the risk of infections.
    • Thiotepa may increase the side effects of Chlorambucil.
    • Thalidomide may increase the risk of dangerous blood clots.

Click here to go to Chlorambucil forums.

Reference

  • “Product information. LEUKERAN® (Chlorambucil).” Glaxosmithkline., NC 27709.
  • ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41.
  • Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health and Human Services, 1992, US Dept of Health and Human Services, Public Health Service publication NIH 92-2621.
  • AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591.
  • National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.
  • Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428.
  • Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263.
  • American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.
  • Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685.

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About the Author:

B. Pharm (K.L.E. society's S.V.V. Patil College of Pharmacy, Bengaluru) M. Pharm (Maharishi Arvind Institute of Pharmacy, Jaipur)

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