Chlorambucil is a chemotherapeutic alkylating agent that cross-links the DNA and impairs transcription of the RNA. It is used to treat the following conditions:

• For the treatment of Chronic lymphocytic leukemia (CLL).

• For the management of Hodgkin's and Non-Hodgkin's Lymphomas.

• As Off-Label Use in the treatment of Waldenström macroglobulinemia

Chlorambucil Dose in Adults

Note:

• Patients who received a full course of radiation or myelosuppressive chemotherapy in the past one month should be advised the lowest possible initial dose.
• The maximum dose should not exceed 0.1 mg/kg/day in patients with CLL or lymphoma with bone marrow involvement.

  ---

• Dose in Chronic lymphocytic leukemia (CLL):

  • 0.1 mg/kg/day for 3 - 6 weeks or
  • 0.4 mg/kg pulsed doses administered intermittently, twice weekly, or monthly
  • (The dose may be increased by 0.1 mg/kg/dose until response or toxicity is observed)

• Off-label dosing in CLL:

  • 0.4 mg/kg on day one every 2 weeks
  • The dose may be increased by 0.1 mg/kg with each treatment course to a maximum dose of 0.8 mg/kg and a maximum of 24 cycles or
  • 30 mg/m² on day one every 2 weeks in combination with prednisone or
  • 40 mg/m² on day one every 4 weeks until disease progression or complete remission or response up to a maximum of 12 cycles.

• As off-label use in combination therapy in previously untreated patients with CLL:

  • In combination with obinutuzumab:
    • 0.5 mg/kg on day 1 and day 15 every 28 days for 6 cycles.
  • In combination with ofatumumab:
    • 10 mg/m² once a day for 7 days (days 1 - 7) every 28 days for a minimum of 3 cycles and up to 12 cycles or best response

• Use of Chlorambucil in the treatment of Hodgkin lymphoma:

  • 0.2 mg/kg/day for 3 - 6 weeks

• Use of Chlorambucil in the treatment of Non-Hodgkin lymphomas (NHL):

  • 0.1 mg/kg/day for 3 - 6 weeks

• Off-label use of Chlorambucil in the treatment of Waldenström macroglobulinemia:

  • 0.1 mg/kg/day for at least 6 months or
  • 0.3 mg/kg/day for seven days every 6 weeks for at least 6 months.

Chlorambucil Dose in Childrens

• Use of Chlorambucil in the treatment of Hodgkin lymphoma:

  • Infants older than 7 months, Children, and Adolescents:
    • ChlVPP regimen:
      • 6 mg/m² /day on days 1 - 14 of a 28-day cycle for 6 - 10 cycles in combination with vinblastine, procarbazine, and prednisolone.

• Use of Chlorambucil in treatment of frequently relapsing steroid-sensitive Nephrotic syndrome:

  • Children and Adolescents:
    • 0.1 - 0.2 mg/kg/day once a day orally for 8 weeks to a maximum cumulative dose of 11.2 mg/kg.

Dosing adjustment for toxicity:

Dose adjustment in Adults:

• Skin reactions:
  • Treatment should be discontinued.
• Hematologic toxicity:
  • WBC or platelets below the normal range
    • Reduce the dose
  • Severely depressed WBC or platelet counts
    • Discontinue treatment
  • Persistent neutropenia, thrombocytopenia, or peripheral lymphocytosis:
    • Do not exceed 0.1 mg/kg/day in adults as this is suggestive of bone marrow infiltration.
• Concurrent chemotherapy or radiotherapy within the past four weeks.
  • Treatment should be used cautiously.
  • The dose may be reduced and monitored closely.

Pregnancy Risk Factor D

• Chlorambucil crosses a human placental barrier, and is dangerous for the fetus.
• It can cause renal agenesis and is teratogenic (if used in the first trimester).
• Women who are pregnant should use strict contraception and not get pregnant while on treatment.
• It can affect fertility, resulting in amenorrhea in females and azoospermia in males.[U.S. Boxed Warning].

Use of chlorambucil while breastfeeding

• It is unknown if the drug can be absorbed into breastmilk. 
• Because of possible adverse effects on the infants breastfeeding, either breastfeeding should be continued or discontinue the drug.

Chlorambucil Dose in Renal Disease:

Dose adjustment has not been recommended by the manufacturer, however, some experts recommend the following adjustment as per renal clearance.

•  CrCl of more than 50 mL/minute.
  • No dose adjustment is required
• CrCl 10 - 50 mL/minute.
  • Administer 75% of the dose
• CrCl of less than 10 mL/minute.
  • Administer 50% of the dose
• Peritoneal dialysis (PD).
  • Administer 50% of the dose.

Chlorambucil Dose in Liver Disease:

The manufacturer has not recommended any dose adjustment in patients with liver disease, however, dose adjustment is necessary as it is primarily metabolized in the liver.

Common Side Effects of Chlorambucil include:

• Central nervous system:
  • Drug fever
  • Peripheral neuropathy
• Dermatologic:
  • Allergic skin reaction
  • Skin rash
  • Urticaria
• Endocrine & metabolic:
  • Amenorrhea
• Gastrointestinal:
  • Diarrhea
  • Nausea
  • Oral mucosa ulcer
  • vomiting
• Genitourinary:
  • Azoospermia
  • Cystitis
  • Infertility
• Hematologic & oncologic:
  • Anemia
  • Bone marrow depression
  • Bone marrow failure
  • Secondary Leukemia
  • Leukopenia
  • Lymphocytopenia
  • Secondary Malignancies
  • Neutropenia
  • Pancytopenia
  • Thrombocytopenia
• Hepatic:
  • Hepatotoxicity
  • Jaundice
• Hypersensitivity:
  • Angioedema
  • Hypersensitivity reaction
• Respiratory:
  • Interstitial pneumonitis
  • Pulmonary fibrosis
• Miscellaneous:
  • Fever

Contraindication to Chlorambucil include:

• Allergy reactions to chlorambucil and any component of the formulation
• Hypersensitivity reactions to alkylating agents
• Documented resistance against the drug
• You should use it within one month after a complete course of radiotherapy or chemotherapy.

Warnings and Precautions

• Suppression of bone marrow [U.S.-Bound Warning]
  • Chlorambucil can cause severe bone marrow suppression, such as severe neutropenia and peripheral cytopenias.
  • Patients who have had myelosuppressive therapy, radiation therapy, or chemotherapy in the last four weeks can avoid the highest dose or use it as an alternative.
  • Patients with baseline cytopenias should be given a low initial dose.
  • Irreversible bone marrow injury has been linked to doses exceeding 6.5 mg/kg

• Fertility effects [U.S.-Bound Warning]
  • It can cause amenorrhea in females and azoospermia in males, which can lead to irreversible or reversible infertility.
  • It can also be mutagenic or teratogenic for the human foetus.

• Secondary malignancy [U.S.-Bound Warning]
  • It is carcinogenic, and chronic use has been linked to acute myelocytic lymphoma and secondary malignancies.
  • Patients who take higher doses or use it for longer periods of time are more at risk of developing leukemia.

• Seizures
  • Patients who have had seizures, head trauma or are at high risk for seizure should not take the drug.

• Reactions to skin:
  • Severe skin reactions such as erythema multiforme and Stevens Johnson syndrome,, and TEN (toxic epidermal necrosis) can occur. The therapy may be stopped immediately.

• Hepatic impairment
  • It is mostly metabolized in liver, so patients with liver disease should consider dose reductions.

Chlorambucil: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitor:

• Liver function tests weekly
• CBC with differential twice weekly for 3 - 6 months and then once weekly therafter.

How to take Chlorambucil?

It is administered orally as a single daily dose.

Mechanism of action of Chlorambucil:

It is an alkylating compound that interferes with DNA replication and transcription through the process of cross-linking and alkylation of DNA strands. It happens quickly and almost immediately

IntakeEspecially when taken empty stomach. 99 percent of the drug isBind to albuminIt is widely used.

MetabolizedThe liver converts active metabolite, phenylacetic acids mustard, to its active metabolite.

It has been aEliminating half-lifeIt takes approximately 1.5 hours to reach peak plasma concentration and it takes less than one hour.

It isExcretedIn the urine, primarily inactive metabolites.

International Brands of Chlorambucil:

• Chloraminophene
• Clokeran
• Leukeran

Chlorambucil Brands in Pakistan:

No brands available in Pakistan