Leukeran

Reversible pancytopenia was the main finding of inadvertent overdoses of chlorambucil. Neurological toxicity ranging from agitated behavior and ataxia to multiple grand mal seizures has also occurred. As there is no known antidote, the blood picture should be closely monitored and general supportive measures should be instituted, together with appropriate blood transfusions, if necessary. Chlorambucil is not dialyzable.

Oral LD50 single doses in mice are 123 mg/kg. In rats, a single intraperitoneal dose of 12.5 mg/kg of chlorambucil produces typical nitrogen-mustard effects; these include atrophy of the intestinal mucous membrane and lymphoid tissues, severe lymphopenia becoming maximal in 4 days, anemia, and thrombocytopenia. After this dose, the animals begin to recover within 3 days and appear normal in about a week, although the bone marrow may not become completely normal for about 3 weeks. An intraperitoneal dose of 18.5 mg/kg kills about 50% of the rats with development of convulsions. As much as 50 mg/kg has been given orally to rats as a single dose, with recovery. Such a dose causes bradycardia, excessive salivation, hematuria, convulsions, and respiratory dysfunction.

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Store in the refrigerator. Do not freeze.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Do not receive a "live" vaccine while you are being treated with chlorambucil, and for at least 3 months after your treatment ends. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), oral polio, rotavirus, typhoid, varicella (chickenpox), H1N1 influenza, and nasal flu vaccine.

Leukeran is a prescription medication used to treat chronic lymphocytic leukemia (CLL; a type of cancer of the white blood cells). Leukeran is also approved for the treatment of certain lymphomas.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Leukeran there are no specific foods that you must exclude from your diet when receiving Leukeran

Before receiving Leukeran, tell your doctor about all of your medical conditions including if you have:

• liver or kidney disease
• a history of seizures
• an infection
• ever had a head injury
• received radiation or chemotherapy treatment

Tell your doctor if you are allergic to any ingredient in Leukeran or any other medication, especially other alkylating agents.

Tell your doctor if you are pregnant or breastfeeding.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

• Interferes with DNA replication and transcription of RNA; ultimately results in disruption of nucleic acid function.a

• Possesses some immunosuppressive activity, principally due to suppression of lymphocytes.a

• The slowest acting and generally least toxic of the currently available nitrogen mustard derivatives.a

Use Leukeran as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
• To gain the most benefit, do not miss doses.
• You will need to take special care when handling Leukeran. Check with the doctor or pharmacist to see how to handle this medicine.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• Store in a refrigerator. Do not freeze.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Mechanism of Action

Chlorambucil, an aromatic nitrogen mustard derivative, is an alkylating agent. Chlorambucil interferes with DNA replication and induces cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of Bax, an apoptosis promoter.

Pharmacokinetics

In a study of 12 patients given single oral doses of 0.2 mg/kg of Leukeran, the mean dose-adjusted (±SD) plasma chlorambucil Cmax was 492 ± 160 ng/mL, the AUC was 883 ± 329 ng.h/mL, the mean elimination half-life (t½) was 1.3 ± 0.5 hours, and the Tmax was 0.83 ± 0.53 hours. For the major metabolite, phenylacetic acid mustard (PAAM), the mean dose-adjusted (± SD) plasma Cmax was 306 ± 73 ng/mL, the AUC was 1204 ± 285 ng.h/mL, mean t½ was 1.8 ± 0.4 hours, and the Tmax was 1.9 ± 0.7 hours. 
    After single oral doses of 0.6 to 1.2 mg/kg, peak plasma chlorambucil levels (Cmax) are reached within 1 hour and the terminal elimination half-life (t½) of the parent drug is estimated at 1.5 hours.
    Absorption: Chlorambucil is rapidly and completely (>70%) absorbed from the gastrointestinal tract. Consistent with the rapid, predictable absorption of chlorambucil, the inter-individual variability in the plasma pharmacokinetics of chlorambucil has been shown to be relatively small following oral dosages of between 15 and 70 mg (2-fold intra-patient variability, and a 2 to 4 fold interpatient variability in AUC). The absorption of chlorambucil is reduced when taken after food. In a study of ten patients, food intake increased the median Tmax by 2-fold and reduced the dose-adjusted Cmax and AUC values by 55% and 20%, respectively.
    Distribution: The apparent volume of distribution averaged 0.31 L/kg following a single 0.2 mg/kg oral dose of chlorambucil in 11 cancer patients with chronic lymphocytic leukemia. 
    Chlorambucil and its metabolites are extensively bound to plasma and tissue proteins. In vitro, chlorambucil is 99% bound to plasma proteins, specifically albumin. Cerebrospinal fluid levels of chlorambucil have not been determined. 
    Metabolism: Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard, which has antineoplastic activity. Chlorambucil and its major metabolite undergo oxidative degradation to monohydroxy and dihydroxy derivatives. 
    Excretion: After a single dose of radiolabeled chlorambucil (14C), approximately 20% to 60% of the radioactivity appears in the urine after 24 hours. Again, less than 1% of the urinary radioactivity is in the form of chlorambucil or phenylacetic acid mustard.