Chlorambucil

[Section Outline]

Chronic Lymphocytic Leukemia
Non-Hodgkin's Lymphoma
Hodgkin's Disease
Macroglobulinemia
Nephrotic Syndrome
Other Uses

Chlorambucil has been used in the treatment of various malignant and nonmalignant diseases; however, because of its carcinogenic potential, the drug should be used with extreme caution, if at all, in the treatment of nonmalignant diseases. (See Cautions: Mutagenicity and Carcinogenicity.)

Chronic Lymphocytic Leukemia

Chlorambucil, in combination with prednisone or alone, is a treatment of choice for chronic lymphocytic leukemia (CLL);106,108 many clinicians recommend the combination unless corticosteroids are contraindicated. In patients with early-stage disease, treatment may be deferred since immediate chemotherapy with chlorambucil, with or without steroids, has not been shown to prolong survival.109,110 Therapy is usually reserved for patients with progressive, symptomatic disease as evidenced by enlarged or painful lymph nodes or spleen; fever, night sweats, anorexia, weight loss, recurrent infections, or cutaneous lesions such as nonspecific leukemids; acquired autoimmune hemolytic anemia or thrombocytopenia; and/or granulocytopenia, thrombocytopenia, or anemia secondary to increasing impairment of bone marrow function. Combination chemotherapy has not been shown to prolong survival compared with single-agent therapy with chlorambucil in patients with advanced-stage CLL.110

A complete remission, as evidenced by the disappearance of symptoms and physical manifestations of the disease, normalization of complete blood cell counts (including the differential cell count), and less than 30% lymphocytes in the bone marrow, occurs in only about 10% of patients receiving chlorambucil alone. However, a partial response, characterized as an increase in the quality of life and decreased splenomegaly, leukocyte counts, and lymphadenopathy, occurs in 60-70% of previously untreated patients receiving the drug. Similar response rates appear to be produced by either intermittent or continuous regimens of chlorambucil; however, myelosuppression appears to be less severe with intermittent regimens. In addition, since chlorambucil has been associated with the development of acute leukemia, especially following long-term therapy (see Cautions: Mutagenicity and Carcinogenicity), some clinicians prefer intermittent rather than continuous administration of the drug; however, no comparative data are available.

The combination of chlorambucil and prednisone appears to produce a higher percentage of complete remissions and partial responses than either agent used alone and is an effective regimen when administered intermittently or continuously. Prednisone may be especially useful in the treatment of patients with extensive bone marrow involvement, bone marrow failure, or acquired autoimmune hemolytic anemia or thrombocytopenia; in such patients, corticosteroids are often given for up to 4 weeks or longer before chlorambucil is administered.

Response to therapy may occur gradually over several months. Therefore, regardless of the treatment regimen and schedule used, many clinicians believe that a minimum of 3-12 months of therapy is necessary in order to obtain the optimum response. Although it has not been clearly established, patients who achieve a complete remission appear to have a prolonged duration of survival. In patients who achieve a complete remission or in those whose symptoms are controlled, it has not been shown that continuous maintenance therapy is more effective in prolonging survival than intermittent therapy which is administered only when the disease relapses or progresses.

Non-Hodgkin's Lymphoma

In the treatment of advanced non-Hodgkin's lymphomas, chlorambucil alone has reportedly produced complete remission in 10-15% of patients and partial response in 40-70% of patients. However, combination chemotherapy that includes other agents is generally considered more effective, particularly in the treatment of advanced non-Hodgkin's lymphomas of unfavorable histology.

Chlorambucil alone may be useful in the treatment of patients with advanced non-Hodgkin's lymphomas of favorable histology (e.g., nodular lymphocytic lymphoma or diffuse well-differentiated lymphocytic lymphoma).106,111 Although combination chemotherapy has generally been reported to produce a higher percentage of complete remission in the treatment of advanced non-Hodgkin's lymphomas of favorable histology, single alkylating-agent therapy may be at least as effective in prolonging survival. Some clinicians recommend single alkylating-agent therapy for the treatment of most patients with these lymphomas, reserving combination chemotherapy for those patients who are symptomatic or have bulky or threatening disease. In addition, some clinicians have reported that an intermittent regimen of chlorambucil has produced complete remission in 60-70% of patients with nodular lymphocytic lymphomas; the effect of such therapy on survival remains to be established. Occasionally, chlorambucil alone may also be useful in the treatment of elderly or debilitated patients with advanced non-Hodgkin's lymphomas who are unable to tolerate the adverse effects of combination chemotherapy.

Hodgkin's Disease

Although chlorambucil is labeled for use in the treatment of Hodgkin's disease,107 combination therapy that does not include chlorambucil currently is preferred for this cancer.106

Chlorambucil has been used alone or with other antineoplastic agents in the treatment of advanced Hodgkin's disease. In order to minimize nausea, vomiting, and myelosuppression, chlorambucil has been used (instead of mechlorethamine hydrochloride) in combination chemotherapy regimens similar to the MOPP (mechlorethamine, vincristine sulfate, procarbazine hydrochloride, prednisone) regimen. Although such regimens are well tolerated and appear to produce response rates similar to those produced by the MOPP regimen, the effect on survival has not been established.

Occasionally, chlorambucil alone may be useful in the treatment of some patients with advanced Hodgkin's disease who are elderly or debilitated and unable to tolerate the adverse effects of combination chemotherapy, or whose disease is resistant to MOPP and other combination chemotherapy regimens.

Macroglobulinemia

Chlorambucil is considered by many clinicians to be the drug of choice for the treatment of (Waldenstrom's) macroglobulinemia†. Chemotherapy for the treatment of macroglobulinemia is usually administered when extensive bone marrow infiltration, anemia, marked splenomegaly and lymphadenopathy, bleeding manifestations, and/or signs related to increased plasma viscosity (e.g., visual disturbances associated with retinal hemorrhage, lassitude, and confusion) occur. Chlorambucil has been used effectively alone or with prednisone in continuous or intermittent regimens. When chlorambucil is administered with prednisone, about 75% of patients manifest disappearance of palpable lymphadenopathy, normalization of lymphocyte counts from elevated pretreatment values, and a decrease in immunoglobulin M (IgM) peaks to less than 50% of pretreatment values.

Nephrotic Syndrome

Chlorambucil has also been used effectively with prednisone in the treatment of children with minimal-change nephrotic syndrome† (lipoid nephrosis, idiopathic nephrotic syndrome of childhood) who have frequent relapses, require corticosteroid therapy to maintain remissions, or whose disease is resistant to steroid therapy. In most of these children, chlorambucil and prednisone therapy has induced long-term remissions and decreased the frequency of relapses. Although this type of nephrotic syndrome only occasionally occurs in adults, it is treated similarly.

Some clinicians have reported that children with frequent relapses, in whom maintenance of remission is not steroid-dependent, can be treated effectively with steroids and chlorambucil or cyclophosphamide, while those who are steroid-dependent do not appear to benefit from such therapy. However, other clinicians have reported that children with steroid-dependent disease are at least as responsive to chlorambucil and prednisone therapy as children with frequent relapses who do not require steroids to maintain remissions. These conflicting results may be due in part to differences in study design and criteria; further evaluation is needed. Some clinicians have also noted that some children older than 4 years of age whose duration of disease is longer than 3 years appear to be more likely to respond to chlorambucil and prednisone therapy than younger children or those with a shorter duration of disease.

The relative efficacy of chlorambucil and cyclophosphamide in the treatment of children with minimal-change nephrotic syndrome remains to be clearly established. However, because of the potentially serious adverse hematologic and gonadal effects of chlorambucil , most clinicians believe that the drug should be used only in the treatment of those children with severe, steroid-dependent or frequently relapsing disease who have intolerable adverse effects (e.g., uncontrollable hypertension, severe diabetes mellitus, severe growth retardation) from steroid therapy or whose disease is steroid-resistant. Some clinicians prefer cyclophosphamide.

Chlorambucil has also been used with good results alone or with steroids in the treatment of some patients with lupus glomerulonephritis†. The drug also has been used in an alternating regimen with steroids for the treatment of adults with membranous glomerulonephritis and nephrotic syndrome†,100,105 and has produced sustained remissions in many patients.105

Other Uses

Chlorambucil has been used by some clinicians with good results in the treatment of intractable idiopathic uveitis† and related conditions including Behcet's syndrome†; autoimmune hemolytic anemias associated with cold agglutinins†; systemic lupus erythematosus†; severe, chronic rheumatoid arthritis† unresponsive to conventional therapies; and vasculitis† associated with rheumatoid arthritis. Chlorambucil also has been used in the treatment of mycosis fungoides†112 and sarcoidosis†.

Dosage and Administration ⬆ ⬇

[Section Outline]

Administration
Dosage

Administration

Chlorambucil is administered orally.107

Dosage

General Dosage

Dosage of chlorambucil must be based on the clinical and hematologic response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects. Clinicians should consult published protocols for the dosage of chlorambucil and other chemotherapeutic agents and the method and sequence of administration.

Dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.107

Dosage adjustment and/or temporary discontinuance may be necessary because of concomitant therapy (e.g., radiation, immunosuppressive drugs) and/or hematologic status. (See Cautions: Precautions and Contraindications.)

For dosage of chlorambucil in the treatment of specific diseases, consult the appropriate sections that follow.

The usual adult dosage of chlorambucil recommended by the manufacturer for initiation of therapy or for short courses of treatment is 0.1-0.2 mg/kg given as a single daily dose for 3-6 weeks; the usual dosage is 4-10 mg daily.107

The manufacturer states that the initial dosage should be reduced if chlorambucil is administered within 4 weeks after a full course of radiation therapy or chemotherapy or if pretreatment leukocyte or platelet counts are depressed from bone marrow disease.107 In patients whose bone marrow is infiltrated with lymphocytes or is hypoplastic due to disease or previous myelosuppressive therapy, the daily dose should not exceed 0.1 mg/kg (about 6 mg for the average patient).107

Many clinicians believe that short courses of chlorambucil therapy are safer than continuous maintenance therapy, although both are effective.107 The manufacturer states that continuous therapy with chlorambucil may appear to maintain patients who are actually in remission and suggests that it may be desirable to withdraw the drug in such patients in order to determine if maintenance therapy is necessary.107 If maintenance therapy is used, the daily dosage should not exceed 0.1 mg/kg and may be as low as 0.03 mg/kg; the usual maintenance dosage is 2-4 mg daily or less depending upon the hematologic status of the patient.107

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Hematologic Toxicity

Hematologic status must be carefully monitored in patients receiving chlorambucil.107 (See Precautions for information on monitoring of hematologic status. Also see Cautions: Hematologic Effects.) Although initial, mild depression of neutrophil counts does not usually necessitate interruption of therapy, dosage of chlorambucil should be reduced if the leukocyte count decreases abruptly or if the leukocyte and platelet counts decrease to less than normal values.107 Because neutrophil counts may continue to fall for 10 days following the last dose, and because irreversible bone marrow damage may occur, the drug should be discontinued if more severe bone marrow depression occurs .107 Treatment of severe myelosuppression may consist of supportive therapy, anti-infectives for complicating infections, and transfusions with blood components.

Dermatologic Toxicity

Chlorambucil should be discontinued promptly if skin reactions occur.107

Chronic Lymphocytic Leukemia

The usual dosage may be used for the treatment of chronic lymphocytic leukemia; however, patients usually require only 0.1 mg/kg daily.107 Alternatively, many clinicians recommend intermittent dosage schedules of chlorambucil, preferably with prednisone. In order to minimize the adverse GI effects of single, high doses of chlorambucil given in these intermittent dosage schedules, the drug may be given at bedtime with an antiemetic.

Many clinicians administer chlorambucil as a single daily dose once every 2 weeks. In this biweekly regimen, the initial dose of chlorambucil is 0.4 mg/kg; the dose is increased by 0.1 mg/kg every 2 weeks until a response and/or myelosuppression occurs. Subsequent dosage is adjusted to produce mild myelosuppression. Varying dosages of prednisone (e.g., 80 mg daily for 5 days) have been administered in this biweekly regimen in conjunction with each dose of chlorambucil. Single chlorambucil doses up to 130 mg have been given in this regimen without severe bone marrow toxicity.

Other clinicians administer chlorambucil as a single daily dose once every 4 weeks. In this regimen, the initial dose of chlorambucil is 0.4 mg/kg; the dose is increased by 0.2 mg/kg every 4 weeks until a response and/or myelosuppression occurs. Subsequent dosage is adjusted to produce mild myelosuppression. In this regimen, prednisone is given daily for the first 6 weeks of treatment. The initial prednisone dosage of 0.8 mg/kg daily is tapered gradually during this period to 0.2 mg/kg daily, and then prednisone is temporarily discontinued; beginning with the third dose of chlorambucil, prednisone is given in a dosage of 0.5-0.8 mg/kg daily for 7 days in conjunction with each dose of chlorambucil. Single chlorambucil doses as high as 1.5-2 mg/kg have been given in this regimen without severe bone marrow toxicity.

Regardless of the regimen and schedule used in the treatment of chronic lymphocytic leukemia, therapy is usually continued for 3-12 months in order to obtain the optimum response. In patients who achieve a complete remission, therapy is generally discontinued after 1 year of treatment and restarted when the disease relapses. In patients who have only a partial response, therapy may be continued as necessary.

Non-Hodgkin's Lymphoma and Hodgkin's Disease

The usual dosage may be used for the treatment of advanced non-Hodgkin's lymphomas or advanced Hodgkin's disease; however, patients with non-Hodgkin's lymphomas usually require only 0.1 mg/kg daily while those with Hodgkin's disease usually require 0.2 mg/kg daily.

Alternatively, in the treatment of nodular lymphocytic lymphomas, some clinicians recommend an intermittent dosage schedule and administer chlorambucil alone as a single daily dose once every 2 weeks. In this biweekly regimen, the initial dose of chlorambucil is 0.4 mg/kg; the dose is increased by 0.1 mg/kg every 2 weeks until a response and/or myelosuppression occurs. Subsequent dosage is adjusted to produce mild myelosuppression. In order to minimize adverse GI effects of single, high doses, the drug may be given at bedtime with an antiemetic. Although optimum duration of such therapy has not been established, treatment is generally continued for 6-12 months. In patients who achieve a complete remission, some clinicians discontinue therapy after 1 year of treatment and restart it when the disease relapses, while other clinicians may continue treatment.

Macroglobulinemia

In the treatment of macroglobulinemia†, chlorambucil has been administered continuously or intermittently. Some clinicians have maintained a large number of patients on 2-10 mg of chlorambucil daily for up to 9 years. Other clinicians recommend a 10-day regimen of chlorambucil (8 mg/m² daily) in combination with prednisone (30 mg/m² daily). This 10-day regimen is repeated every 6-8 weeks for as long as necessary. In patients who have a marked response, the regimen may be discontinued after 18 months and restarted when relapse occurs.

Nonmalignant Diseases

If chlorambucil is used in the treatment of nonmalignant disease, the risk of inducing a malignancy must be considered. (See Cautions: Mutagenicity and Carcinogenicity.)

In the treatment of children with minimal-change nephrotic syndrome†, the usual dosage of chlorambucil has been 0.1-0.2 mg/kg daily with varying dosages of prednisone for 8-12 weeks in one course of therapy. In some patients, an additional course of therapy may be necessary. The lowest effective dosage of chlorambucil remains to be established. Because of the potentially serious adverse hematologic and gonadal effects of chlorambucil, some clinicians have recommended a maximum total dosage of 14 mg/kg in one course of therapy, while other clinicians have recommended a maximum total dosage of 8.2 mg/kg in one course of therapy (approximately equivalent to 6 weeks of treatment with daily doses of 0.2 mg/kg). (See Cautions: Pregnancy, Fertility, and Lactation.)

In the treatment of intractable idiopathic uveitis† and related conditions including Behcet's syndrome, the usual dosage of chlorambucil has been 6-12 mg daily or 0.1-0.2 mg/kg daily, generally for at least 1 year.101,102,103,104 Dosages up to 20 mg daily have been used temporarily in patients with rapidly deteriorating visual acuity or CNS involvement.103

Cautions ⬆ ⬇

[Section Outline]

Hematologic Effects
GI Effects
Nervous System Effects
Dermatologic and Sensitivity Reactions
Pulmonary Effects
Other Adverse Effects
Precautions and Contraindications
Pediatric Precautions
Geriatric Precautions
Mutagenicity and Carcinogenicity
Pregnancy, Fertility, and Lactation

Hematologic Effects

Adverse hematologic effects are the major and dose-limiting effects of chlorambucil. (See Dosage Modification for Toxicity and Contraindications for Continued Therapy: Hematologic Toxicity in Dosage and Administration: Dosage. Also see Precautions for information on monitoring of hematologic status.) In usual doses, myelosuppression generally occurs gradually, is moderate in severity, and is usually reversible following discontinuance of the drug. Leukopenia, resulting from neutropenia and slowly progressive lymphopenia, occurs in many patients receiving chlorambucil. Thrombocytopenia and anemia may also occur.

When chlorambucil is administered continuously in a short course of therapy, leukopenia does not generally appear until after the third week of treatment; thrombocytopenia may precede leukopenia. The neutrophil count may continue to decrease for up to 10 days after the last dose of chlorambucil. In one study in which chlorambucil was administered daily for 6 weeks to patients with various neoplasms, leukopenia and thrombocytopenia usually occurred 1-2 weeks after discontinuance of the drug in those patients who developed adverse hematologic effects. Following discontinuance of a short course of therapy with continuous dosing of chlorambucil, leukopenia and thrombocytopenia generally last 1-2 weeks but may persist for 3-4 weeks. Following administration of a single, high dose of chlorambucil, leukocyte and platelet nadirs generally occur after 7-14 days with recovery in 2-3 weeks; thrombocytopenia may persist slightly longer than leukopenia. Adverse hematologic effects appear to be less severe following intermittent administration of single, high doses of chlorambucil than following continuous administration of the drug. With excessive doses or prolonged therapy, pancytopenia and irreversible bone marrow damage may occur; the manufacturer states that these effects may occur when total chlorambucil dosage approaches 6.5 mg/kg (about 450 mg in an adult) in one course of therapy with a continuous dosing regimen. However, some clinicians believe that these effects are not so clearly predictable from the total chlorambucil dosage administered and could even occur with lower cumulative dosages.

Treatment of severe myelosuppression may consist of supportive therapy, antibiotics for complicating infections, and transfusions with blood components.

GI Effects

Chlorambucil appears to be relatively free of adverse GI effects unless single doses of 20 mg or more are administered. Adverse GI effects include nausea, vomiting, gastric discomfort or abdominal pain, anorexia, and diarrhea. Adverse GI effects are usually mild, last less than 24 hours, and disappear despite continued treatment; however, nausea and weakness have persisted up to 7 days in some patients following a single, high dose of the drug. If necessary, nausea and vomiting may usually be controlled with antiemetics. Oral ulceration has also been reported.

Nervous System Effects

Focal and/or generalized seizures have occurred in children and adults following therapeutic doses, high single doses, or overdosage (see Acute Toxicity: Manifestations) and also in children receiving chlorambucil for the treatment of nephrotic syndrome. In children with nephrotic syndrome, seizures reportedly occurred 6-90 days after beginning treatment with chlorambucil in a dosage of 0.2-0.7 mg/kg daily. Seizures usually occurred as single episodes and were initially focal but rapidly progressed to generalized activity; EEGs showed focal abnormalities or diffuse slowing. These seizures generally resolved spontaneously with no apparent residual neurologic damage. Focal seizures with transient, flaccid hemiparesis have also been reported in one adult with chronic lymphocytic leukemia following repeated challenges with chlorambucil. Rarely, globus hystericus and fatigue have been associated with the drug. Tremors, muscular twitching, myoclonia, confusion, agitation, ataxia, flaccid paralysis, and hallucinations have been reported rarely in patients receiving chlorambucil; these adverse effects resolve following discontinuance of the drug.107 Peripheral neuropathy has been reported rarely in patients receiving chlorambucil.

Dermatologic and Sensitivity Reactions

Allergic reactions, including urticaria and angioedema, have been reported following initial or subsequent dosing with chlorambucil.107 Rash or dermatitis (sometimes maculopapular or urticarial), pruritus, or occurrence or exacerbation of herpes zoster may occur in patients receiving chlorambucil. Hypersensitivity reactions, including rash progressing to erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been reported rarely. Chlorambucil should be discontinued promptly if skin reactions occur.107 Alopecia, or generalized urticaria and erythema with marked periorbital edema, also has been reported rarely.

Pulmonary Effects

Like other alkylating agents (e.g., busulfan, cyclophosphamide), chlorambucil may rarely cause a syndrome of bronchopulmonary dysplasia and interstitial pneumonitis or pulmonary fibrosis. This syndrome has occurred following intermittent or prolonged continuous dosing of chlorambucil and was manifested as cough, fever, rales, dyspnea, respiratory distress, and/or hypoxia. In some patients, the pulmonary complications resolved following discontinuance of the drug and administration of steroids; in other patients, however, pulmonary complications progressed despite discontinuance of chlorambucil and some deaths occurred.

Other Adverse Effects

As a result of extensive purine catabolism accompanying rapid cellular destruction, hyperuricemia may occur in patients receiving chlorambucil, and serum uric acid concentrations should be monitored. Hyperuricemia and its potential adverse effects may be minimized or prevented by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.

Rarely, hepatotoxicity with jaundice and elevated serum alkaline phosphatase and AST (SGOT) concentrations has been attributed to chlorambucil. Rare cases of drug fever and sterile cystitis have also been associated with the drug.

Precautions and Contraindications

Chlorambucil is a toxic drug with a low therapeutic index. A therapeutic response is not likely to occur without some adverse effect. In therapeutic doses, however, chlorambucil is generally the least toxic of the presently available nitrogen mustard derivatives. The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents.

Women of childbearing potential should be advised to avoid becoming pregnant during chlorambucil therapy.107

Chlorambucil should be used with caution in patients with a history of seizures or head trauma or those receiving other potentially epileptogenic drugs.107 It appears that there is an increased risk of chlorambucil-induced seizures in children with nephrotic syndrome and in patients receiving high single doses of chlorambucil.

Hematologic status must be monitored carefully in patients receiving chlorambucil, and dosage reduction or discontinuance of therapy may be necessary.107 (See Dosage Modification for Toxicity and Contraindications for Continued Therapy: Hematologic Toxicity, in Dosage and Administration: Dosage.) The manufacturer recommends that complete blood cell counts, including hemoglobin concentration, total and differential leukocyte counts, and quantitative platelet concentration, be performed at least once weekly during chlorambucil therapy.107 In addition, the manufacturer recommends that leukocyte counts be performed 3-4 days after each of the weekly complete blood counts during the first 3-6 weeks of therapy.107 The manufacturer states that it is dangerous to allow a patient to go more than 2 weeks without hematologic and clinical evaluation during chlorambucil therapy.107

The manufacturer states that chlorambucil should not be administered in the usual dosage and should be used with extreme caution within 4 weeks after a full course of radiation therapy or chemotherapy.107 However, chlorambucil may be given in the usual dosage concomitantly with small doses of radiation administered at isolated foci remote from the bone marrow.107

Patients should be informed of the risk of the major toxicities associated with chlorambucil, including hypersensitivity, drug fever, myelosuppression, hepatic toxicity, infertility, seizures, GI toxicity, and secondary malignancies.107 Patients who receive myelosuppressive drugs experience a high frequency of infections as well as possible hemorrhagic complications, and these complications are potentially fatal. Patients receiving chlorambucil should be instructed to notify a clinician if they experience any of the following: skin rash, bleeding, fever, jaundice, persistent cough, seizures, nausea, vomiting, amenorrhea, or unusual lumps or masses.107

The administration of live vaccines to immunocompromised patients should be avoided.107

Chlorambucil is contraindicated in patients with known hypersensitivity to the drug or in patients whose disease was resistant to prior therapy with the drug. The manufacturer states that there may be cross-sensitivity between chlorambucil and other alkylating agents manifested as rash. Chlorambucil should be discontinued promptly in patients who develop skin reactions.

Pediatric Precautions

The safety and efficacy of chlorambucil in children have not been established; however, the drug has been used in pediatric patients when the benefits were believed to outweigh the potential risks.

Geriatric Precautions

Safety and efficacy of chlorambucil in geriatric patients have not been studied specifically to date.107 While clinical experience has not revealed age-related differences in response, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.107 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.107

Mutagenicity and Carcinogenicity

Chlorambucil is potentially mutagenic. The drug has caused chromatid or chromosome damage in humans.107

Chlorambucil is carcinogenic in mice and has been associated with the development of acute leukemia in patients with malignant or nonmalignant diseases, especially with prolonged continuous dosing of the drug. A total dosage of chlorambucil below which there is no risk of inducing a secondary malignancy has not been established.107 Many patients receiving chlorambucil who developed acute leukemia also received other antineoplastic agents or radiation therapy.107 A relatively high frequency of epithelial neoplasms has been reported in patients receiving chlorambucil.109 Rarely, chlorambucil has also been associated with the development of solid tumors or plasma cell dyscrasias. Although the benefits of chlorambucil therapy in the palliative treatment of malignant diseases are generally believed to outweigh the potential risks, the possibility of development of a secondary malignancy must be considered. Because of the potential risks, the drug should be used with extreme caution, if at all, in the treatment of nonmalignant diseases.

Pregnancy, Fertility, and Lactation

Pregnancy

Chlorambucil can cause fetal harm when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus. It has been reported that in 2 women who received chlorambucil during early pregnancy and had therapeutic abortions, the fetuses had unilateral absence of a kidney and ureter; this anomaly has also been observed in the offspring of pregnant rats receiving the drug. Therefore, chlorambucil should be used during pregnancy only in conditions such as life-threatening situations or for disease for which safer drugs cannot be used or are ineffective. If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.

Fertility

Chlorambucil has potentially serious adverse effects on the gonads. A high incidence of infertility, which generally appears to be irreversible, has been reported in prepubertal and pubertal males receiving chlorambucil. A total dosage of the drug below which there is no risk of inducing infertility has not been established. Limited data indicate that infertility generally appears to occur at total dosages greater than 11 mg/kg; however, it has occurred at lower total dosages. In one study in prepubertal and pubertal males, azoospermia occurred in all patients receiving a total dosage greater than 25 mg/kg, while conservation of fertility appeared to be related to a total dosage less than 7 mg/kg. In another study, most prepubertal males who developed oligospermia or azoospermia received a total dosage greater than 16.8 mg/kg. In this study, those patients who developed normal sperm counts received an average total dosage of 10.2 mg/kg. In general, overall pubertal development appears to progress normally in males who receive chlorambucil before puberty; however, testicular atrophy may occur and persist. Although serum testosterone concentrations are usually normal, serum concentrations of follicle-stimulating hormone are often substantially increased. Progressive but reversible oligospermia has occurred in adult males receiving a total dosage up to 400 mg of chlorambucil, but azoospermia and testicular germinal aplasia have occurred with higher total dosage. Azoospermia may be permanent in adult males receiving a total dosage greater than 400 mg, but spermatogenesis has returned in some of these patients 3-58 months after discontinuing the drug. In general, overall pubertal development also appears to progress normally in females who receive chlorambucil before puberty; however, potential effects on ovarian function remain to be evaluated. Chlorambucil may suppress ovarian function; amenorrhea has been reported in pubertal and adult females receiving the drug.

Lactation

It is not known if chlorambucil is distributed into milk. Because of the potential for serious adverse reactions from chlorambucil in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.

Other Information ⬆ ⬇

[Section Outline]

Pathogenesis
Manifestations
Treatment
Absorption
Distribution
Elimination
Chemistry
Stability

Acute Toxicity

Limited information is available on the acute toxicity of chlorambucil.

Pathogenesis

The oral LD₅₀ of chlorambucil is 123 mg/kg in mice.

Manifestations

Acute overdosage of chlorambucil in 4 young children has been reported. Within 1.5-4 hours after ingestion of 1.5-5 mg/kg, vomiting, ataxia, abdominal pain, muscle twitching, and/or agitation developed. In one child who ingested 5 mg/kg, coma (lasting 24 hours) and major motor seizures developed within 5 hours after ingestion; multiple seizures occurred in the first 24 hours, but the child markedly improved with complete disappearance of signs and symptoms within 24-48 hours. In another child, multifocal myoclonic seizures occurred within 16 hours but cleared spontaneously within 32 hours without anticonvulsant therapy. In another child, lethargy, irritability, and periods of hyperactivity with jerky movements occurred over 48 hours and subsided within 3-5 days. No apparent residual neurologic damage occurred in any of the children. Moderate pancytopenia generally developed with nadirs occurring 1-6 weeks after the ingestion, and recovery of the bone marrow occurring 3-7 weeks after the ingestion. One adult also reportedly ingested a total of 280 mg of chlorambucil (4.1 mg/kg) over 5 days and was asymptomatic except for a moderate pancytopenia which was reversible within 30 days.

Treatment

Treatment of chlorambucil intoxication consists of general supportive therapy. If ingestion of the drug is recent and the patient is fully conscious, emesis should be induced. If the patient is comatose, having seizures, or has lost the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Administration of activated charcoal after gastric lavage and/or emesis may be useful. The manufacturer reports that chlorambucil is not dialyzable.107 Complete blood counts should be performed at least 3 times weekly for at least 3 weeks and until myelosuppressive effects have subsided. Administration of appropriate blood components may be necessary.

Pharmacology

As an alkylating agent, chlorambucil interferes with DNA replication and transcription of RNA, and ultimately results in the disruption of nucleic acid function.

In vitro studies have shown that the major metabolite of chlorambucil (phenylacetic acid mustard), which is also a bifunctional alkylating compound, has antineoplastic activity against some neoplastic human cell lines that is approximately equal to that of chlorambucil. Therefore, the major metabolite of chlorambucil may contribute to the in vivo antitumor activity of the drug. Chlorambucil also possesses some immunosuppressive activity, principally due to its suppression of lymphocytes. The drug is the slowest acting and generally least toxic of the presently available nitrogen mustard derivatives.

Pharmacokinetics

Absorption

Chlorambucil is rapidly and completely absorbed from the GI tract.107 Following single oral doses of 0.6-1.2 mg/kg, peak plasma concentrations of chlorambucil are reached within 1 hour.107 In a limited number of patients given a single oral dose of chlorambucil 0.2 mg/kg, an average peak plasma chlorambucil concentration of 492 ng/mL (adjusted to a dose of 12 mg) was reached at about 0.83 hours, and a mean peak plasma concentration of phenylacetic acid mustard (the major metabolite of chlorambucil) of 306 ng/mL (adjusted to a chlorambucil dose of 12 mg) occurred at approximately 1.9 hours.107 The area under the plasma concentration-time curve (AUC) of phenylacetic acid mustard was about 1.36 times greater than the AUC of chlorambucil.107

Distribution

Distribution of chlorambucil in humans has not been fully characterized, but the drug and its metabolites appear to be extensively bound to plasma and tissue proteins.107 In vitro, chlorambucil is approximately 99% bound to plasma proteins, mainly albumin.107 Although adverse CNS effects have been reported (see Cautions: Nervous System Effects), it is not known if chlorambucil crosses the blood-brain barrier.107

Based on evidence of human teratogenicity, chlorambucil apparently crosses the placenta.107 It is not known if the drug or its metabolites are distributed into milk.107

Elimination

Following single oral doses of 0.6-1.2 mg/kg, the terminal elimination half-life of chlorambucil was estimated to be 1.5 hours.107 In a limited number of patients given a single oral dose of chlorambucil 0.2 mg/kg, the average terminal plasma half-lives of chlorambucil and phenylacetic acid mustard (the principal metabolite) were approximately 1.3 and 1.8 hours, respectively.107

Chlorambucil is rapidly and extensively metabolized in the liver, principally to phenylacetic acid mustard, which is pharmacologically active.107 Phenylacetic acid mustard is formed by β-oxidation of the butyric acid side chain of chlorambucil, apparently via the dehydrogenated intermediate 3,4-dehydrochlorambucil. Chlorambucil and phenylacetic acid mustard apparently undergo spontaneous degradation in vivo, forming monohydroxy and dihydroxy derivatives.107

Chlorambucil is excreted in the urine almost completely as metabolites.107 Because chlorambucil is almost completely metabolized, urinary excretion of the drug and its metabolites is low.107 About 15-60% of a single oral dose of chlorambucil is excreted in the urine within 24 hours; less than 1% of the dose is excreted in the urine as unchanged chlorambucil or phenylacetic acid mustard, and the remainder is excreted apparently as the monohydroxy and dihydroxy derivatives of chlorambucil and phenylacetic acid mustard.107

The manufacturer states that chlorambucil is not dialyzable.107

Chemistry and Stability

Chemistry

Chlorambucil, a nitrogen mustard derivative, is a bifunctional alkylating agent. The drug occurs as an off-white, slightly granular powder, is very slightly soluble in water, and has apparent pK_a values of 1.3 and 5.8.

Stability

Chlorambucil tablets should be stored at 2-8°C.107

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Cautions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

Chlorambucil

Copyright ⬆ ⬇

References ⬆