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chlorambucil
Chlorambucil was synthesized in 1953. It is an aromatic derivative of mechlorethamine, is closely related in structure to melphalan and is a bifunctional alkylating agent. DNA alkylation by the reactive ethylenimonium radical results in breaks in the DNA molecule as well as cross-linking of the twin strands, thus interfering with DNA replication and transcription of RNA. Like other alkylators, chlorambucil is cell cycle phase-nonspecific. The immunosuppressive activity of chlorambucil is due to its suppression of lymphocytes.
| Bioavailability | oral: Yes, bioavailability 70-80%. Food decreases bioavailability by 10-20%. |
Rapidly cleared from plasma; tissue distribution fairly homogeneous; crosses placenta; found in ascitic fluid.
| Cross blood brain barrier? | no information found, but can cause seizures in high doses. |
| Volume of distribution | 0.14-0.24 L/kg |
| PPB | 99% (albumin) |
Extensively metabolized in liver by the hepatic microsomal enzyme oxidation system
| Active metabolites | phenylacetic acid mustard. |
| Inactive metabolites | Yes |
Extremely low urinary excretion. Chlorambucil and its metabolites are probably not dialysable.
| Urine | 15-60% in 24 hours; less than 1% as intact drug / active metabolite. |
| Half-life | 1.5 hours |
- Monotherapy in chronic lymphocytic leukemia
- Monotherapy or combination therapy in:
- Non-Hodgkin’s lymphoma (e.g. follicular, MALT, mantle cell lymphoma, Waldenstrom’s macroglobulinemia)
- Hodgkin’s lymphoma (palliative)
Emetogenic Potential:
Extravasation Potential: Not applicable
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Dermatological | Rash (may be severe) | E | |||
| Gastrointestinal | Diarrhea (infrequent) | I | |||
| Mucositis (infrequent) | E | ||||
| Nausea, vomiting (infrequent) | I | ||||
| Hematological | Immunosuppression | E | |||
| Myelosuppression ± infection, bleeding (may be severe) | E | ||||
| Hepatobiliary | Hepatotoxicity | D | |||
| Hypersensitivity | Drug reaction | I | |||
| Metabolic / Endocrine | Tumor lysis syndrome | I | |||
| Neoplastic | Leukemia (secondary) (or other malignancies) | L | |||
| Nervous System | Neurotoxicity | E | |||
| Peripheral neuropathy | L | ||||
| Seizure (Rare, with high doses, prior history) | E | ||||
| Reproductive and breast disorders | Infertility | L | |||
| Respiratory | Pneumonitis | E | |||
| Urinary | Cystitis (sterile) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
Myelosuppression is more severe following continuous administration than intermittent high dose chlorambucil and is dose-related. Prolonged therapy or excessive doses may result in pancytopenia or irreversible bone marrow damage.
Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly proliferative tumours of massive burden (e.g. some leukemias and lymphomas), can be minimized with allopurinol and hydration. In hospitalized patients, the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.
Pulmonary toxicity similar to other alkylating agents can occur, including interstitial pulmonary fibrosis or pneumonitis. Signs and symptoms are dyspnea, dry cough, fever, rales and tachypnea developing over a 1-2 month period. It is usually associated with prolonged therapy (6-24 months) and related to a total dose of >2 g. Partial recovery can occur within several weeks after discontinuing therapy and administration of steroids. In other patients, pulmonary complications progress and some deaths have occurred.
Children with nephrotic syndrome and patients receiving high pulse doses or with a prior history of seizures may have an increased risk of seizures, and should be closely monitored. Rare, focal and/or generalized seizures have also occurred in patients receiving therapeutic daily doses.
Rarely, skin rash may occur and result in Stevens-Johnson Syndrome, toxic epidermal necrolysis or erythema multiforme. Chlorambucil should be discontinued immediately if skin reactions occur. Patients with a history of rash with other alkylating agents may have an increased risk of rash.
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy.
Continuous regimens:
- Induction: 0.1-0.2 mg/kg/day PO (CLL - until white cell count 10 x 109/L; for 4-8 weeks for NHL)
- Maintenance: After 4-week “rest”: 0.03-0.1 mg/kg/day PO adjusted to tolerance
Intermittent regimens:
- q28d: 6 mg/m2/d PO for 7-14 days
Modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 " Dosage Modification for Hematologic and Non-Hematologic Toxicities."
| Toxicity and grade | Action | Dose when restart |
| Severe myelosuppression/ bone marrow failure |
Discontinue |
N/A |
|
Grade 3 hematologic |
Hold* |
↓ by 33% |
|
Grade 4 hematologic, febrile neutropenia or thrombocytopenic bleeding |
Hold* |
↓ by 33% or Discontinue |
|
Grade 3 non-hematologic |
Hold* |
↓ by 33% |
|
Skin or pulmonary toxicity or Grade 4 non-hematologic |
Discontinue |
N/A |
No adjustment required, but monitor carefully as at increased risk of myelosuppression.
|
Creatinine Clearance (mL/min)
|
% Dose
|
|
10-50
|
75%
|
|
<10
|
50%
|
- Oral self-administration; drug available by outpatient prescription.
- Keep drug refrigerated; do not freeze
Chlorambucil is contraindicated in patients who are resistant to the drug or who have developed hypersensitivity to it; there may be cross-sensitivity with other alkylating agents (especially rash) .
Should not be used within 4 weeks of a full course of radiation therapy or chemotherapy. Administer with caution if bone marrow is severely depressed and in patients with seizure disorders. Avoid live vaccines.
Chlorambucil has been shown to have teratogenic, mutagenic and carcinogenic properties in experimental models and should not be used in pregnancy. Adequate contraception must be used by both sexes, during treatment and for at least 6 months after chlorambucil cessation. Chlorambucil is known to cross the placenta. Breast feeding is not recommended because of the potential secretion of chlorambucil into breast milk. Secondary malignancies have been reported.
Both reversible and permanent sterility have been observed in both sexes. Children receiving chlorambucil before puberty generally have a normal progression of puberty. In males, however, testicular atrophy may occur and persist.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Phenylbutazone | ↑ the toxicity of chlorambucil | Unknown | Modify chlorambucil doses |
| Succinylcholine | prolonged apnea | inhibition of serum cholinesterase | decrease dose of succinylcholine |
| Live vaccines | systemic viral infection risk | immunosuppression | avoid / caution |
| Monitor Type | Monitor Frequency |
|---|---|
| CBC | Weekly or twice weekly |
| Toxicity assessment (seizures, GI, hypersensitivity, TLS, infection, bleeding, pulmonary) | Routinely |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
| Liver function tests | Periodic |
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 98.
Bauwens D, Maerevoet M, Michaux L, et al. Activity and safety of combined rituximab with chlorambucil in patients with mantle cell lymphoma. British Journal of Haematology 2005; 131: 338–40.
Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA).
Chlorambucil: e-Drugdex, Micromedex Healthcare Series.
McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 987-90.
Martinelli G, Laszlo D, Bertolini F, et al. Chlorambucil in combination with induction and maintenance rituximab is feasible and active in indolent non-Hodgkin’s lymphoma. British Journal of Haematology 2003; 123: 271–7.
Radford JA, Rohatiner AZS, Ryder WDJ, et al. ChlVPP/EVA Hybrid Versus the Weekly VAPEC-B Regimen for Previously Untreated Hodgkin’s Disease. J Clin Oncol 2002; 20: 2988-2994.
Product Monograph: Leukeran® (chlorambucil). Triton Pharma Inc. Canada, November 29, 2010.
Product Monograph: Leukeran® (chlorambucil). GlaxoSmithKline Inc. USA, October 2011.
June 2019 Updated emetic risk category
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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