Chlorambucil is a medication that belongs to the class of drugs known as alkylating agents. It is primarily used as a chemotherapy drug in the treatment of certain types of cancers, particularly chronic lymphocytic leukemia (CLL), lymphomas, and Hodgkin's disease. Chlorambucil works by interfering with the growth and division of cancer cells, thereby slowing down or stopping the spread of the disease.

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

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Chlorambucil Dose in Adults

Note:

• If a person has recently received high-dose radiation or other drugs that can affect the bone marrow, the initial dose of chlorambucil should be reduced.
• When there is involvement of lymphocytes in the bone marrow (such as in chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma), the maximum daily dose of chlorambucil is 0.1 mg per kilogram of body weight.
• It is preferable to use chlorambucil for shorter periods of treatment, but if maintenance therapy is necessary, the maximum daily dose remains 0.1 mg per kilogram of body weight.

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Chlorambucil dose in the treatment of Chronic lymphocytic leukemia (CLL):

In the treatment of Chronic lymphocytic leukemia (CLL), the dose of chlorambucil can vary depending on different factors. Here are some dosage regimens used in CLL:

Oral administration:

• The recommended dose is 0.1 mg per kilogram of body weight per day for a period of 3 to 6 weeks.
• Alternatively, pulsed doses of 0.4 mg per kilogram of body weight can be given intermittently, either biweekly or monthly. The dose can be increased by 0.1 mg/kg with each treatment course until a response or toxicity is observed.

Off-label dosing for CLL:

• A dose of 0.4 mg per kilogram of body weight is given on day 1 every 2 weeks. If tolerated, the dose can be increased by 0.1 mg/kg with each treatment course, up to a maximum dose of 0.8 mg/kg. This can be continued for a maximum of 24 cycles.
• Another off-label dosing option is 30 mg/m² on day 1 every 2 weeks in combination with prednisone.
• A different regimen is 40 mg/m² on day 1 every 4 weeks until disease progression, complete remission, or a response plateau is reached, for a maximum of 12 cycles.

Off-label combinations for previously untreated CLL patients:

• In combination with obinutuzumab, the recommended dose of chlorambucil is 0.5 mg/kg on days 1 and 15 every 28 days for 6 cycles.
• When combined with ofatumumab, the dose of chlorambucil is 10 mg/m² once daily for 7 days (days 1 to 7) every 28 days for a minimum of 3 cycles. It can be continued up to 12 cycles or until the best response is achieved. The dose may need to be reduced to 7.5 mg/m²/day and then further to 5 mg/m²/day if there is hematologic toxicity.

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Chlorambucil dose in the treatment of Hodgkin lymphoma:  

• In the treatment of Hodgkin lymphoma, the recommended dose of chlorambucil is typically higher compared to the dose used for chronic lymphocytic leukemia (CLL).
• The standard oral dose for Hodgkin lymphoma is 0.2 mg per kilogram of body weight per day. This dose is usually given for a period of 3 to 6 weeks.

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Chlorambucil dose in the treatment of non-Hodgkin lymphomas (NHL):

• In the treatment of non-Hodgkin lymphomas (NHL), the recommended dose of chlorambucil is similar to that used for chronic lymphocytic leukemia (CLL) but may have variations based on the specific subtype and stage of NHL.
• The standard oral dose of chlorambucil for NHL is 0.1 mg per kilogram of body weight per day. This dose is typically administered for a period of 3 to 6 weeks.

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Chlorambucil as off label dose in the treatment of Waldenström macroglobulinemia:

In the off-label use of chlorambucil for the treatment of Waldenström macroglobulinemia, there are two common dosage regimens:

Continuous therapy:

• The recommended dose is 0.1 mg per kilogram of body weight per day.
• This dose is taken orally on a daily basis and should be continued for at least 6 months.

Intermittent therapy:

• The recommended dose is 0.3 mg per kilogram of body weight per day.
• This higher dose is taken orally for 7 consecutive days every 6 weeks.
• This 7-day treatment cycle should also be continued for at least 6 months.

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Chlorambucil Dose in Childrens

Note: In oncology, including the use of chlorambucil, the dosage and frequency can vary depending on the specific treatment protocol or phase. Different treatment protocols may have their own recommended doses and schedules for administering chlorambucil.

Chlorambucil dose in the treatment of Hodgkin lymphoma:

In infants aged 7 months and older, children, and adolescents with Hodgkin lymphoma, the ChlVPP regimen is sometimes used. This regimen involves the combination of chlorambucil with vinblastine, procarbazine, and prednisolone. The dosage of chlorambucil in this regimen is as follows:

• Oral administration: 6 mg per square meter of body surface area per day.
• The treatment is given on days 1 to 14 of a 28-day cycle.
• This regimen is typically administered for 6 to 10 cycles.

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

In children and adolescents with frequently relapsing steroid-sensitive nephrotic syndrome, chlorambucil is occasionally used. However, it's important to note that there is limited data available on its effectiveness, and it is not considered a preferred agent due to a higher incidence of adverse effects without providing greater efficacy compared to other treatments.

• If chlorambucil is used, the recommended oral dosage is typically between 0.1 to 0.2 mg per kilogram of body weight once daily.
• This dose is taken for a duration of 8 weeks, with a maximum cumulative dose of 11.2 mg per kilogram.

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Dosing adjustment for toxicity:  

Dosing adjustments for toxicity with chlorambucil are typically based on experience in adult patients, and specific recommendations for pediatric patients are limited. It is important to refer to the specific treatment protocol or guidelines for managing toxicity in pediatric patients.

In adult patients, the following dosing adjustments may be considered for toxicity:

• Skin reactions:
  • If a patient develops skin reactions, treatment with chlorambucil should be discontinued.

• Hematologic toxicity:

• If white blood cell (WBC) or platelet counts fall below the normal range, a dose reduction may be necessary.
• In cases of severely depressed WBC or platelet counts, treatment with chlorambucil should be discontinued.
• Persistently low neutrophil or platelet counts or peripheral lymphocytosis may suggest bone marrow infiltration. If infiltration is confirmed, the dose should not exceed 0.1 mg/kg/day in adults.

• Concurrent or recent chemotherapy/radiotherapy:
  • If chlorambucil is being used concurrently or within 4 weeks of chemotherapy or radiotherapy, it should be initiated cautiously.
  • The dose may need to be reduced, and close monitoring is essential.

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Pregnancy Risk Factor D

• Chlorambucil has been shown to cause birth defects in animal studies and can pass through the placenta in humans.
•  There have been reports of adverse effects on the kidneys, such as unilateral agenesis, when exposure occurs during the first trimester of pregnancy.
•  It is important for women who can become pregnant to avoid getting pregnant while receiving chlorambucil treatment.
•  The use of chlorambucil can affect fertility and is likely to have mutagenic (causing genetic changes) and teratogenic (causing birth defects) effects.
•  Chromosomal damage has been documented as well.
•  In males, chlorambucil can lead to reversible or irreversible sterility in prepubertal and pubertal stages, azoospermia (absence of sperm) in adult males, and in females, it can cause amenorrhea (absence of menstrual periods).
•  Autopsy findings have shown fibrosis, vasculitis, and depletion of primordial follicles in the ovaries.

Use of chlorambucil while breastfeeding

• The presence of chlorambucil in breast milk is currently unknown.
•  Since there is a possibility of serious adverse reactions in the nursing infant, the decision to continue or discontinue breastfeeding should carefully consider the benefits of chlorambucil treatment for the mother.

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Chlorambucil Dose in Renal Disease:

The manufacturer's labeling does not provide specific dosage adjustments for renal impairment with chlorambucil.

However, studies have shown that renal elimination of chlorambucil and its active metabolite is minimal, and renal impairment is unlikely to significantly affect elimination.

Based on recommendations from Aronoff in 2007:

• For adults with a creatinine clearance (CrCl) greater than 50 mL/minute, no dosage adjustment is necessary.
• For adults with a CrCl between 10 to 50 mL/minute, a reduced dose of 75% is recommended.
• For adults with a CrCl less than 10 mL/minute or receiving peritoneal dialysis (PD), a further reduced dose of 50% is recommended.

On the other hand, Kintzel in 1995 suggests that based on the pharmacokinetics of chlorambucil, dosage adjustment is not necessary for renal impairment.

Chlorambucil Dose in Liver Disease:

• Chlorambucil is primarily metabolized in the liver.
• While dosage reduction may be necessary in patients with hepatic impairment, the manufacturer's labeling does not provide specific dosage adjustments due to insufficient data.
• It is important to exercise caution and closely monitor patients with hepatic impairment when administering chlorambucil.

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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

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Contraindication to Chlorambucil include:

• Chlorambucil should not be used in individuals who have a known hypersensitivity to chlorambucil or any of its components. It is also contraindicated in individuals with hypersensitivity to other alkylating agents, as cross-hypersensitivity may occur. Additionally, chlorambucil should not be used in individuals who have demonstrated resistance to the drug.
• In the Canadian labeling, there is an additional contraindication not mentioned in the US labeling. Chlorambucil should not be used within 4 weeks of completing a full course of radiation therapy or chemotherapy.

Warnings and Precautions

Suppression of bone marrow [U.S.-Bound Warning]

• Chlorambucil carries a significant risk of causing severe bone marrow suppression, which can lead to low levels of various blood cells, including neutrophils (a type of white blood cell).
• Neutropenia, a severe reduction in neutrophil count, can occur.
• To minimize this risk, the initial dosage of chlorambucil should be reduced if the patient has recently received myelosuppressive or radiation therapy within the past 4 weeks, or if their baseline leukocyte (white blood cell) or platelet count is already low.
• It's important to note that irreversible damage to the bone marrow may occur if the total dose of chlorambucil approaches 6.5 mg/kg.
• Progressive lymphopenia (a decrease in lymphocyte count) may also develop, but it generally improves quickly after chlorambucil is discontinued.
• Close monitoring of blood cell counts is necessary during treatment to detect any signs of bone marrow suppression and adjust the dosage as needed to minimize the risk.

Fertility effects [U.S.-Bound Warning]

• Chlorambucil has significant effects on fertility.
• It is likely to have mutagenic (causing genetic changes) and teratogenic (causing birth defects) properties, and there have been documented cases of chromosomal damage.
• In males who have not yet reached puberty or are in their pubertal stage, chlorambucil can cause reversible or irreversible sterility, meaning their ability to have children may be temporarily or permanently affected.
• In adult males, chlorambucil can cause azoospermia, which means there is an absence of sperm in the semen.
• In females, chlorambucil can lead to amenorrhea, which is the absence of menstrual periods.

Secondary malignancy [U.S.-Bound Warning]

• Chlorambucil has been found to have carcinogenic properties, meaning it can increase the risk of developing secondary malignancies, including acute myelocytic leukemia.
• The risk of developing leukemia is higher with prolonged treatment and higher cumulative doses of chlorambucil.
• It is important to be aware of this potential risk when considering long-term therapy with chlorambucil, patients should be closely monitor patients for any signs or symptoms of secondary malignancies during and after treatment.

Seizures

• Seizures have been reported as a possible side effect of chlorambucil use.
• Patients who have a history of nephrotic syndrome and receive high pulse doses of chlorambucil are at a higher risk of experiencing seizures.
• It is important to exercise caution when using chlorambucil in patients who have a history of seizure disorder or head trauma.

Reactions to skin:

• In rare cases, severe skin reactions such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported with the use of chlorambucil.
• If a patient experiences any skin reaction while taking chlorambucil, it is important to discontinue the medication promptly.
• These severe skin reactions can be serious and potentially life-threatening, so immediate medical attention should be sought if any skin reaction occurs during treatment with chlorambucil.

Hepatic impairment

• Chlorambucil is primarily metabolized in the liver.
• Therefore, in patients with hepatic impairment (reduced liver function), it is important to consider reducing the dosage of chlorambucil.
• The liver plays a crucial role in metabolizing medications, and impaired liver function can affect the breakdown and elimination of chlorambucil from the body.
• Adjusting the dosage in patients with hepatic impairment helps to ensure that the medication is appropriately processed and reduces the risk of potential side effects or toxicity.
• It is recommended for patients who can evaluate the individual's liver function and determine the appropriate dosage adjustment based on the specific circumstances.
• Regular monitoring and close medical supervision are important to ensure the safe and effective use of chlorambucil in patients with hepatic impairment.

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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

Risk Factor C (Monitor therapy).
Chloramphenicol Ophthalmic	May increase the toxic/adverse effects of Myelosuppressive Agents.
CloZAPine	CloZAPine's toxic/adverse effects may be exacerbated by myelosuppressive agents. Particularly, there may be an increase in the risk of neutropenia.
Coccidioides immitis skin test	Coccidioides immitis Skin Test may be affected by immunosuppressants.
Denosumab	Might increase the toxic/adverse effects of Immunosuppressants. In particular, there may be an increase in the risk of serious infections.
Ocrelizumab	May increase the immunosuppressive effects of Immunosuppressants.
Pidotimod	Pidotimod's therapeutic effects may be diminished by immunosuppressants.
Promazine	May increase the myelosuppressive effects of Myelosuppressive Drugs.
Siponimod	Siponimod's immunosuppressive effects may be enhanced by taking immunosuppressants.
Sipuleucel - T	Sipuleucel T's therapeutic effects may be diminished by immunosuppressants
Tertomotide	Tertomotide's therapeutic effects may be diminished by immunosuppressants.
Trastuzumab	May increase the neutropenic effects of Immunosuppressants.
Risk Factor D (Consider therapy modifications)
Baricitinib	Baricitinib's immunosuppressive effects may be enhanced by immunosuppressants. Baricitinib should not be used in combination with immunosuppressants like azathioprine and cyclosporine. It is permissible to use methotrexate antirheumatically or nonbiologic disease-modifying antirheumatic drug (DMARDs), concurrently.
Echinacea	Might decrease the therapeutic effects of Immunosuppressants.
Fingolimod	Fingolimod may be immunosuppressed by immunosuppressants. When possible, avoid the use of fingolimod with other immunosuppressants. Patients should be closely monitored for any additive immunosuppressant effects, such as infections, if they are used together.
Leflunomide	Leflunomide's toxic/adverse effects may be exacerbated by immunosuppressants. The risk of hematologic toxicities such as pancytopenia and agranulocytosis may increase. Patients on immunosuppressants should not be given a leflunomide loading dosage. Patients who are receiving leflunomide or another immunosuppressant must be checked for bone marrow suppression at minimum monthly.
Lenograstim	Antineoplastic Agents can reduce the therapeutic effects of Lenograstim. Management: Lenograstim should be avoided 24 hours prior to and 24 hours following the completion of myelosuppressive, cytotoxic chemotherapy.
Lipegfilgrastim	Antineoplastic agents may reduce the therapeutic effects of Lipegfilgrastim. Management: It is important to avoid the simultaneous use of lipegfilgrastim with myelosuppressive, cytotoxic chemotherapy. After myelosuppressive chemotherapy has been completed, lipegfilgrastim must be given at least 24 hours.
Nivolumab	Nivolumab's therapeutic effects may be diminished by immunosuppressants.
Palifermin	Can increase the toxic/adverse effects of Antineoplastic Agents. In particular, oral mucositis can be more severe and prolonged. Management: Avoid administering palifermin for 24 hours prior to, during, or after infusion of myelotoxic chemotherapy.
Roflumilast	May increase the immunosuppressive effects of Immunosuppressants.
Tofacitinib	Tofacitinib's immunosuppressive effects may be enhanced by immunosuppressants. Management: It is permissible to use methotrexate (or nonbiologic disease-modifying antirheumatic drug (DMARDs), concurrently with antirheumatic doses. This warning appears to be particularly targeted at more potent immunosuppressants.
Vaccines (Inactivated).	Immunosuppressants can reduce the therapeutic effects of Vaccines (Inactivated). Management: The effectiveness of vaccines may be decreased. All age-appropriate vaccines must be completed at least two weeks before you start an immunosuppressant. Re-vaccinate anyone who was vaccinated while on immunosuppressant therapy.
Risk Factor X (Avoid Combination)
BCG (Intravesical).	The therapeutic effects of BCG (Intravesical) may be diminished by immunosuppressants
BCG (Intravesical).	Myelosuppressive agents may reduce the therapeutic effects of BCG (Intravesical).
Cladribine	May increase the immunosuppressive effects of Immunosuppressants.
Cladribine	May increase the myelosuppressive effects of Myelosuppressive Drugs.
Deferiprone	Deferiprone may have a neutropenic effect that myelosuppressive agents can increase.
Dipyrone	May increase the toxic/adverse effects of Myelosuppressive Agents. In particular, there may be an increase in the risk of pancytopenia and agranulocytosis.
Natalizumab	Natalizumab's toxic/adverse effects may be exacerbated by immunosuppressants. Particularly, concurrent infections may increase.
Pimecrolimus	May increase the toxic/adverse effects of Immunosuppressants
Tacrolimus - Topical	May increase the toxic/adverse effects of Immunosuppressants
Vaccines (Live).	Immunosuppressants can increase the toxic/adverse effects of Vaccines (Live). Immunosuppressants can decrease the therapeutic effects of Vaccines. Management: Avoid the use of live organism vaccines that are immunosuppressant-resistant; live-attenuated vaccinations should be avoided for at least three months.

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Monitoring Parameter:

• Liver function tests should be conducted regularly to assess the impact of chlorambucil on liver function.
• Complete blood cell counts (CBC) with differential should be performed weekly, with specific attention to white blood cell (WBC) counts. During the initial 3 to 6 weeks of treatment, WBC counts should be monitored twice weekly.
• These monitoring measures help to evaluate the effects of chlorambucil on liver function and blood cell counts, ensuring the safety and effectiveness of the medication.
• Regular monitoring and close medical supervision are important to detect any abnormalities or adverse effects and to optimize the management of chlorambucil treatment.

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How to take Chlorambucil?

• Chlorambucil is typically administered orally.
• It can be taken as a single daily dose.

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Mechanism of action of Chlorambucil:

• Chlorambucil is an alkylating agent that works by interfering with the replication of DNA (genetic material) and the transcription of RNA (which helps in protein synthesis).
• It does this by chemically modifying and cross-linking the strands of DNA, which disrupts their normal structure and function.
• This interference with DNA and RNA processes ultimately impairs the growth and division of cells, particularly cancer cells, leading to their destruction.

Absorption:

• Chlorambucil is rapidly and completely absorbed (>70%) from the gastrointestinal tract.
• However, its absorption can be reduced when taken with food.

Distribution:

• The volume of distribution (V) of chlorambucil is approximately 0.3 L/kg.
• This indicates that it is distributed throughout the body.

Protein binding:

• Chlorambucil is highly protein-bound, with approximately 99% of the drug binding to albumin.
• Protein binding helps to transport and distribute the drug throughout the body.

Metabolism:

• Chlorambucil is extensively metabolized in the liver.
• Its primary metabolic pathway leads to the formation of an active metabolite called phenylacetic acid mustard.
• This active metabolite contributes to the therapeutic effects of chlorambucil.

Half-life elimination:

• The half-life of chlorambucil elimination is approximately 1.5 hours.
• For the active metabolite, phenylacetic acid mustard, the half-life is around 1.8 hours.
• The half-life represents the time it takes for half of the drug or metabolite to be eliminated from the body.

Time to peak, plasma:

• Chlorambucil reaches its peak concentration in the blood within 1 hour of administration.
• The active metabolite, phenylacetic acid mustard, reaches its peak concentration within approximately 1.9 ± 0.7 hours.

Excretion:

• Chlorambucil and its metabolites are primarily excreted in the urine.
• Within 24 hours, approximately 20% to 60% of the drug is eliminated, with the majority being in the form of inactive metabolites.
• Less than 1% of the drug or phenylacetic acid mustard is excreted unchanged in the urine.

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International Brands of Chlorambucil:

• Chloraminophene
• Clokeran
• Leukeran

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Chlorambucil Brands in Pakistan:

No brands available in Pakistan