Chlorambucil

Chlorambucil is an antineoplastic/ alkylating agent belonging to the pharmacological class of nitrogen mustards.

Chlorambucil is a broad spectrum of antitumor activity approved by the FDA for treating chronic lymphocytic leukaemia (CLL), Hodgkin's and non-Hodgkin's lymphomas.

Chlorambucil is rapidly and almost completely absorbed in the gastrointestinal tract, with reduced absorption when taken with food. It has a volume of distribution around 0.3 L/kg, and approximately 99% of the drug binds to plasma proteins, mainly albumin. Extensive hepatic metabolism forms the active metabolite, phenylacetic acid mustard. Chlorambucil primarily undergoes urinary excretion.

Chlorambucil's most common side effects include decreased blood cells (red, white, and platelets), anaemia (low number of red blood cells), infection, nausea and vomiting.

The molecule is available in India, the United States, Canada, the United Kingdom, Italy, Australia, Germany, France, Belgium and Spain.

Chlorambucil is an antineoplastic/ alkylating agent belonging to the pharmacological class of nitrogen mustards.

In exerting their anticancer effects, alkylating agents utilize three distinct mechanisms. Initially, they attach alkyl groups to DNA bases, causing fragmentation as repair enzymes endeavour to replace the alkylated bases. This process hinders DNA synthesis and RNA transcription. Subsequently, these agents induce DNA damage by forming cross-links, obstructing DNA separation for synthesis or transcription. Finally, alkylating agents actively cause mispairing of nucleotides, resulting in mutations. These multifaceted actions actively disrupt the normal functioning of rapidly dividing cells, especially cancer cells, positioning alkylating agents as an indispensable class of chemotherapy drugs crucial in treating cancer.

Chlorambucil is available in the form of oral tablets.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily, and it can be taken with or without food as directed.

Chlorambucil can be used for the following health conditions:

• Chronic Lymphatic (Lymphocytic) Leukemia / Blood cancer
• Hodgkin's Lymphoma
• Chronic Lymphatic (Lymphocytic) Leukemia (off-label use in children)
• Non-Hodgkin's lymphoma
• Waldenstrom's macroglobulinaemia
• Other off-label: Behcet's disease-related uveitis and meningoencephalitis; various NHL; idiopathic membranous nephropathy; RA

• In Blood Cancer: Blood cancer, commonly known as leukaemia, affects the tissues that create blood and weakens the immune system. Chlorambucil inhibits the growth and proliferation of cancer cells and their death. Consult the physician about the advantages and disadvantages of this firm's highly poisonous medication. To stay hydrated during this treatment, one should refrain from alcohol and consume lots of water.
• Hodgkin’s disease: A form of blood cancer called lymphoma, which originates in the lymphatic system, is Hodgkin's disease. The lymphatic system aids in the immune system's ability to eliminate waste and combat infections. Chlorambucil inhibits the growth and proliferation of cancer cells and their death. Blood cancer, commonly known as leukaemia, affects the tissues that create blood and weakens the immune system. Chlorambucil inhibits the growth and proliferation of cancer cells and their death.
• Non-Hodgkin's lymphoma: This alkylating drug, Chlorambucil, inhibits the proliferation of malignant cells, which is beneficial in non-Hodgkin lymphoma. It obstructs cell division and triggers apoptosis by altering the DNA structure. Chlorambucil is used in treating several non-Hodgkin lymphoma types, which helps enhance patient outcomes and control the disease.
• Waldenstrom's macroglobulinaemia: Chlorambucil inhibits the formation of malignant cells, damages DNA, prevents division, and triggers apoptosis, all of which benefit Waldenstrom's macroglobulinemia. It is used to treat this illness, improving patient outcomes and aiding in disease control.

Chlorambucil, an alkylating drug, is crucial in various blood cancers.

• In leukaemia, it hinders the growth of cancerous cells, weakening the immune system.
• For Hodgkin's disease, a lymphoma affecting the lymphatic system, and non-Hodgkin's lymphoma, Chlorambucil obstructs malignant cell proliferation, altering DNA structure to induce apoptosis.
• In Waldenstrom's macroglobulinemia, Chlorambucil prevents cell formation, damages DNA, inhibits division, and triggers apoptosis, enhancing patient outcomes and disease control. Patients are advised to stay hydrated and abstain from alcohol during treatment.

Orally: Chlorambucil is usually administered orally as a tablet, twice daily, with or without food; adjust dosage according to patient response and severity of condition. It's advisable to swallow the tablets whole with a full glass of water. Patients should refrain from crushing or chewing the tablets.

Individuals must adhere strictly to the prescribed dosage and administration schedule. Patients are also advised to consult their healthcare provider about the medication's benefits and potential side effects.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablets: 2mg, 5mg.

Chlorambucil is available in the form of oral tablets.

Dose Adjustment in Adult Patients:

Lymphocytic (chronic lymphatic) Leukemia: 0.1 mg/kg every day for three to six weeks or

0.4 mg/kg (increasing every two weeks by 0.1 mg/kg/dose until response or toxicity is seen) or

0.4 mg/kg (updated every month by 0.1 mg/kg/dose until response is seen) or

Continuous daily doses of 0.03-0.1 mg/kg

If given to patients with bone marrow illness or within four weeks of the completion of a full course of radiation therapy or myelosuppressive therapy, lower the initial dose.

Not to surpass 0.1 mg/kg/day if lymphocytes infiltrate the bone marrow

Hodgkin's Lymphoma: 0.2 mg/kg each day for three to six weeks or

0.4 mg/kg (increasing every two weeks by 0.1 mg/kg/dose until response or toxicity is seen) or

0.4 mg/kg (increasing every month by 0.1 mg/kg/dose until toxicity or response is seen) or

Continuous daily doses of 0.03-0.1 mg/kg

If given to patients with bone marrow illness or within four weeks of the completion of a full course of radiation therapy or myelosuppressive therapy, lower the initial dose.

Not to surpass 0.1 mg/kg/day if lymphocytes infiltrate the bone marrow.

Individuals with chronic illnesses, including cancer, should prioritize a diet rich in protein, healthy fats, whole grains, and essential vitamins and minerals. Emphasizing plant-based proteins, such as nuts, seeds, beans, and legumes, can offer vital nutrients during chemotherapy and other cancer treatments. Maintaining a healthy weight is crucial, achieved through regular, low-strain exercises and a balanced diet. Adequate sleep is essential for overall well-being. It's imperative to avoid smoking and alcohol consumption. Eliminating fast and fried foods, processed meats, refined carbs, and added sugars further supports a healthy lifestyle. Adopting these practices actively contributes to managing chronic illnesses and promoting overall health.

The dietary restriction should be individualized as per patient requirements.

• Patients with diseases that have previously shown resistance to Chlorambucil shouldn't be treated with it. The medication shouldn't be administered to patients who have shown signs of hypersensitivity to Chlorambucil. Between Chlorambucil and other alkylating drugs, there may be cross-hypersensitivity (skin rash).
• Lactating

Individuals with a history of seizures or head trauma or those concurrently using other potentially epileptogenic drugs should exercise caution with this medication. It is potentially mutagenic, carcinogenic, and teratogenic, posing risks during pregnancy and may also impact fertility. Severe myelosuppression is a notable side effect, requiring lower dosages in cases of liver failure. Cross-hypersensitivity with other alkylating agents should be considered. Dosage reduction is advisable in preexisting myelosuppressive conditions or if white blood cell or platelet counts fall below normal. Use within four weeks of radiation or cytotoxic chemotherapy is discouraged, and precautions against pregnancy should be observed.

Avoid alcohol consumption while taking Chlorambucil.

Avoid use during breastfeeding.

It is not recommended during pregnancy, especially in the first trimester.

The adverse reactions related to Chlorambucil can be categorized as:

Hematologic: Anemia, leukopenia, neutropenia, thrombocytopenia, pancytopenia, and bone marrow suppression are the most frequent adverse effects. Even though bone marrow suppression is common, if the chlorambucil is stopped early enough, it is usually reversible. On the other hand, reports of irreversible bone marrow failure exist.

Gastrointestinal: Disturbances of the stomach, including vomiting and nausea, diarrhea, and oral

Ulcerations are uncommon.

CNS: Rare side effects of chlorambucil include tremors, muscular twitches, myoclonia, disorientation, agitation, ataxia, flaccid paresis, and hallucinations, which go away when the medication is stopped. Rare cases of therapeutic daily doses, pulse dosing regimens, acute overdoses, and focal or widespread seizures have been documented in both adults and children.

Dermatologic: Following initial or repeated dosage, allergic responses including urticaria and angioneurotic edema have been recorded. There have been reports of skin hypersensitivity, including infrequent cases of skin rash leading to Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme.

Other: There have also been reports of peripheral neuropathy, drug fever, pulmonary fibrosis, hepatotoxicity, jaundice, interstitial pneumonia, sterile cystitis, infertility, leukemia, and secondary malignancies as adverse effects.

The clinically relevant drug interactions of Chlorambucil are briefly summarized here.

Drug-Drug Interactions: Chlorambucil may interact with some vaccines (e.g., influenza, mumps, and BCG vaccines), medications for cancer (e.g., adalimumab), medicines for schizophrenia (e.g., clozapine), medications for treating moderate to severe plaque psoriasis (e.g., Deucravacitinib), medications for treating Multiple Sclerosis (e.g., cladribine), medicines for managing and treating autoimmune conditions (e.g., etanercept), immunomodulating drugs (e.g., fingolimod), and antirheumatic drugs (e.g. leflunomide).

Drug-Food Interactions: Avoid alcohol-based beverages.

Interactions Between Drugs and Diseases: Chlorambucil may interact with infections, myelosuppression (the insufficient production of blood cells or platelets by the bone marrow), pulmonary impairment, hepatic dysfunction, and seizures, among other medical problems.

The most common side effects of Chlorambucil include:

• Anaemia, or reduced red blood cell count
• Reduced blood cells (platelets, white blood cells, and red blood cells)
• Decreased number of neutrophils, or white blood cells
• Seizures (in children)
• Reduced number of white blood cells
• Inhibition of the bone marrow
• Vomiting
• Hair loss
• Vomiting
• Diarrhea
• Mouth ulcer

•Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

If Chlorambucil is given to a pregnant woman, it may harm the fetus. It has been reported that two infants whose mothers took Chlorambucil in the first trimester developed unilateral renal agenesis. Rats fed Chlorambucil during pregnancy developed urogenital abnormalities, including kidney absence. There aren't any sufficient, carefully researched expectant mothers. The patient should be made aware of the possible risk to the fetus if this medication is taken during pregnancy or if the patient falls pregnant while using this medication. It should be urged to women who are capable of bearing children not to get pregnant.

Fertility: Chlorambucil has been linked to reports of infertility as well as reversible and permanent sterility. The duration and dose of treatment are associated with these effects; it is unclear how much below this threshold there is no risk to fertility. Children who take Chlorambucil before reaching puberty typically experience a typical onset of puberty. Testicular atrophy may continue in males.

Possible effects on ovarian function in females are unknown.

•Nursing Mothers

It is unknown if this medication is eliminated in human milk. Given that many medicines are excreted in human milk and that Chlorambucil can cause significant adverse reactions in nursing infants, a decision should be made on whether to stop breastfeeding or to stop taking the medication, taking the mother's need for the medication into consideration.

•Pediatric Use

As per the FDA, safety and effectiveness in the pediatric population have not been established.

Dose Adjustment

Chronic Lymphatic (Lymphocytic) Leukemia (Off-label): 0.1-0.2 mg/kg PO qDay.

•Geriatric Use

There were not enough participants in clinical trials with Chlorambucil over 65 to determine whether their responses differed from those of younger participants. Elderly and younger individuals do not respond differently, according to other documented clinical experiences. Given the higher incidence of reduced hepatic, renal, or cardiac function, concomitant disease, or other drug therapy, dose selection for an elderly patient should generally be conservative and begin at the low end of the dosing range.

Dose Adjustment

Chronic Lymphatic (Lymphocytic) Leukemia: 0.4 mg/kg (increasing by 0.1 mg/kg/dose until response or toxicity noted) or 0.1 mg/kg/day for 3-6 weeks or 0.4 mg/kg every two weeks (increasing by 0.1 mg/kg/dose until response is evident) either monthly or consistently 0.03-0.1 mg/kg/day If given to patients with bone marrow disease or within four weeks of finishing an entire course of radiation therapy, lower the initial dose. Not to surpass 0.1 mg/kg/day if lymphocytes infiltrate the bone marrow.

Hodgkin's Lymphoma: 0.2 mg/kg each day for three to six weeks or

0.4 mg/kg (increasing every two weeks by 0.1 mg/kg/dose until response or toxicity is seen) or

0.4 mg/kg (increasing every month by 0.1 mg/kg/dose until toxicity or response is seen) or

Continuous daily doses of 0.03-0.1 mg/kg

If given to patients with bone marrow illness or within four weeks of the completion of a full course of radiation therapy or myelosuppressive therapy, lower the initial dose.

Not to exceed 0.1 mg/kg/day if lymphocytes infiltrate the bone marrow.

Dose Adjustment in Kidney Impairment Patients:

Less than 1% (including metabolites) excreted in urine, so no dose adjustment required

Dose Adjustment in Hepatic Impairment Patients:

Patients with liver function disorders should take caution while administering Chlorambucil tablets because the drug is extensively metabolized in the liver.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Chlorambucil.

Overconsumption of Chlorambucil could lead to Reversible pancytopenia and neurological toxicity ranging from agitated behaviour and ataxia to multiple grand mal seizures.

Management

If chlorambucil overdose is suspected, immediately seek medical attention. Provide supportive care, monitor vital signs, and implement symptomatic measures. There is no specific antidote; closely monitor the blood picture and consider general supportive measures, including hematopoietic growth factors and blood product transfusions if necessary. Chlorambucil is non-dialyzable. In severe cases, consulting a poison control centre or a medical toxicologist can be beneficial for appropriate guidance and intervention.

Pharmacodynamics: The ability of alkylating agents to add alkyl groups to many electronegative groups under conditions found in cells gives them their name. By directly targeting DNA, they cross-link guanine bases in DNA double-helix strands, halting the formation of tumours. The strands are unable to uncoil and split as a result. Cell division is no longer possible because this is essential for DNA replication. Furthermore, these medications introduce methyl or other alkyl groups onto molecules that shouldn't be there. This prevents the right base pairing and miscodes DNA. Alkylating compounds do not exhibit cell cycle specificity. Three distinct processes are employed by alkylating chemicals to accomplish the same purpose: cell death and impairment of DNA function.

Pharmacokinetics:

•Absorption: The gastrointestinal absorption of Chlorambucil is rapid and nearly complete, with reduced absorption when taken with food. The bioavailability ranges from approximately 70-100%, reaching peak plasma concentration within 1 hour.

•Distribution: Chlorambucil exhibits a distribution volume of about 0.3 L/kg. Approximately 99% of the drug is bound to plasma proteins, predominantly to albumin.

•Metabolism: Extensive hepatic metabolism occurs through monodichloroethylation and β-oxidation processes, primarily forming the active metabolite, phenylacetic acid mustard. Spontaneous degradation may also lead to the formation of other metabolites.

•Excretion: Chlorambucil is excreted primarily through urine, with approximately 20-60% excreted as inactive metabolites and less than 1% as unchanged drug or phenylacetic acid mustard. The terminal elimination half-life is around 1.5 hours. Based on individual patient responses and conditions, regular monitoring and dose adjustments may be necessary.

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