Chlorambucil

BRAND NAMES

• Leukeran: This is the most common brand name for chlorambucil in the United States and other countries.

• Celkeran: This brand is sold in India and other markets.

• Clokeran: This is another brand name available in India.

• Chloramax: This is a brand name sold by GLS Pharma.

• Halkeran: This is a brand name available in some markets.

MECHANISM OF ACTION

Chlorambucil is an alkylating agent that works by attaching alkyl groups to DNA, causing structural changes and cross-links between DNA strands. This prevents DNA replication and RNA transcription, leading to DNA damage. Rapidly dividing cancer cells are particularly affected, and severe DNA damage triggers cell death through apoptosis.

PHARMACOKINETICS:

Absorption

Chlorambucil is efficiently absorbed from the gastrointestinal tract following oral administration. Pharmacokinetic studies have demonstrated that its absorption occurs through passive diffusion, rather than an energy-dependent transport system.

Distribution

Chlorambucil is a lipophilic, bifunctional alkylating agent that is rapidly and extensively distributed throughout the body. After oral administration, it is widely distributed in body tissues, though its concentration is highly dependent on the blood-brain barrier and other biological factors. 

Metabolism

Chlorambucil undergoes rapid and extensive metabolism in the liver, primarily into its main active metabolite, phenylacetic acid mustard. This metabolic process is a key part of how the drug functions and is eliminated from the body.

Excretion

Chlorambucil and its metabolites are primarily eliminated through the urine. Approximately 20% to 60% of the administered dose is excreted within 24 hours, mainly as inactive metabolites, with less than 1% excreted as unchanged drug or PAAM. The elimination half-life of chlorambucil is about 1.5 hours, while PAAM has a half-life of approximately 1.8 hours.

PHARMACODYNAMICS

Chlorambucil is an oral alkylating agent belonging to the nitrogen mustard class of chemotherapy drugs. Its pharmacodynamic action is based on interfering with the structure and function of deoxyribonucleic acid (DNA), which is most effective against rapidly dividing cells like cancer cells. The drug's activity is considered cell cycle-nonspecific because it can damage cancer cells during any phase of their reproductive cycle.

ADMINISTRATION

Chlorambucil is an oral chemotherapy medication that must be administered carefully under the supervision of a physician experienced in using such agents. For safe and effective administration, patients must follow specific guidelines regarding dosage, timing, and handling. 

DOSAGE AND STRENGTH

For adults, the typical dosage of chlorambucil is 0.1 mg per kilogram of body weight per day, administered as a single oral dose for 3 to 6 weeks. This usually translates to 4 to 10 mg daily for the average adult. Children's dosages must be determined by a healthcare provider. In cases of bone marrow involvement, the daily dose should not exceed 0.1 mg/kg, approximately 6 mg for an average adult. Alternative dosing schedules, such as biweekly or monthly pulse dosing, may be employed based on individual patient needs.

DRUG INTERACTIONS

While some medications should never be used together, in certain situations, combining two different medicines may be appropriate even if interactions are possible. In such cases, your doctor might adjust the dosage or implement other precautions. It is crucial that your healthcare provider is informed about all the medications you are taking. The following interactions are highlighted due to their potential significance, but this list may not be exhaustive.

FOOD INTERACTIONS

Certain medications may interact with food, alcohol, or tobacco, potentially affecting their effectiveness or increasing the risk of side effects. For instance, consuming alcohol while on chlorambucil can exacerbate side effects such as liver toxicity and bone marrow suppression. Additionally, some foods may influence how well a medication works. 

CONTRAINDICATIONS

Chlorambucil is contraindicated in patients with known hypersensitivity to the drug or other alkylating agents, as cross-reactivity may occur. It should not be used in individuals whose disease has previously demonstrated resistance to chlorambucil, as re-treatment is unlikely to be effective. Due to its carcinogenic properties, chlorambucil is contraindicated for non-malignant conditions. It is also contraindicated during pregnancy, particularly in the first trimester, as it can cause fetal harm, including urogenital malformations such as unilateral renal agenesis. Additionally, chlorambucil may cause permanent infertility in both men and women and should not be used in individuals planning to conceive.

SIDE EFFECTS

Common Side Effects (Occur in more than 10% of patients)

• Gastrointestinal Issues: Nausea, vomiting, diarrhea, mouth ulcers.

• Hematologic Effects: Anemia (low red blood cell count), thrombocytopenia (low platelet count), leukopenia (low white blood cell count).

• Infections: Increased susceptibility due to lowered white blood cell count.

• Fatigue: Unusual tiredness or weakness.

• Respiratory Symptoms: Shortness of breath, cough, or hoarseness, especially when accompanied by fever or chills.

• Dermatologic Reactions: Skin rash, itching, or hives.

• Oral Symptoms: Sores, ulcers, or white spots on the lips or in the mouth.

• Swelling: Swollen glands or edema in the feet or lower legs.

OVER DOSE

An overdose of chlorambucil (Leukeran) is a medical emergency that primarily causes severe bone marrow suppression and neurological symptoms, such as seizures. Anyone suspected of having taken an overdose must receive immediate medical attention by calling emergency services or a poison control center. 

Immediate effects of an overdose

• Irritability or agitation

• Muscle twitching or jerking

• Exaggerated startle reflex

• Confusion

• Tremors

• Seizures

TOXICITY

Chlorambucil's primary toxicity is bone marrow suppression, leading to reduced production of red blood cells, white blood cells, and platelets. This suppression manifests as anemia, leukopenia, neutropenia, and thrombocytopenia, increasing the risk of infections, bleeding, and fatigue.