Lomustine (Systemic)
VA CLASSIFICATION
Primary: AN100
Commonly used brand name(s): CeeNU.
Another commonly used name is
CCNU .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antineoplastic—
Indications
Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.
Accepted
Tumors, brain, primary (treatment)
[Carcinoma, colorectal (treatment)]1
[Carcinoma, lung, non-small cell (treatment)] or
[Carcinoma, breast (treatment)]—Lomustine is indicated for treatment of both primary and metastatic brain tumors, in patients who have already received appropriate surgical or radiotherapeutic procedures {01} {02}. It is also indicated for treatment of colorectal carcinoma {04} {05}, non–small-cell lung carcinoma {02} {05}, and advanced breast carcinoma after conventional therapy has failed {02}.
Lymphomas, Hodgkin's (treatment)—Lomustine is indicated for treatment of Hodgkin's disease, as secondary therapy in combination with other drugs in patients who relapse while being treated with primary therapy or in patients who fail to respond to primary therapy {01} {02}.
[Multiple myeloma (treatment)]1—Lomustine is also indicated for treatment of multiple myeloma {03}.
[Melanoma, malignant (treatment)]—Lomustine is indicated for treatment of malignant melanoma, alone or in combination with other drugs {02}.
1 Not included in Canadian product labeling.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
233.70
Mechanism of action/Effect:
Lomustine is an alkylating agent of the nitrosourea type. Lomustine (and/or its metabolites) interferes with the function of DNA and RNA. It is cell cycle–phase nonspecific. Lomustine also acts to inhibit DNA synthesis by inhibiting key enzymatic processes.
Absorption:
Well and rapidly absorbed from the gastrointestinal tract.
Distribution:
Crosses the blood-brain barrier.
Protein binding:
Moderate (50%; metabolites).
Biotransformation:
Hepatic; rapid and complete (active metabolites).
Half-life:
Biologic—Approximately 94 minutes.
Chemical—Approximately 15 minutes.
Metabolites—Prolonged; 16 to 48 hours.
Elimination:
Renal (totally as metabolites); some enterohepatic circulation is believed to occur.
Fecal (less than 5%).
Respiratory (10%).
Precautions to Consider
Carcinogenicity/Mutagenicity
Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.
Long-term use of nitrosoureas in humans has been reported to be possibly associated with development of secondary malignancies (acute leukemia) and bone marrow dysplasias {01}.
Lomustine is carcinogenic in rats and mice at the approximate clinical dose and, like other alkylating agents, is probably carcinogenic in humans.
Pregnancy/Reproduction
Fertility—
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.
Lomustine suppresses gonadal function in male rats (at higher than the human dose) and in humans.
Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.
First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.
Other hazards to the fetus include adverse reactions seen in adults.
In general, use of a contraceptive is recommended during cytotoxic drug therapy.
Lomustine is embryotoxic in rats and rabbits and teratogenic in rats at doses approximately equivalent to the human dose.
FDA Pregnancy Category D {01}.
Breast-feeding
Lomustine is distributed into breast milk. Breast-feeding is not recommended during chemotherapy because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).
Pediatrics
Appropriate studies on the relationship of age to the effects of lomustine have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the usefulness of this medication in children are not expected.
Geriatrics
No information is available on the relationship of age to the effects of lomustine in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving lomustine.
Dental
The bone marrow depressant effects of lomustine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.
Lomustine may also cause stomatitis that is associated with considerable discomfort.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Blood dyscrasia–causing medications (see Appendix II ) (leukopenic and/or thrombocytopenic effects of lomustine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of lomustine, if necessary, should be based on blood counts)
» Bone marrow depressants, other (see Appendix II ) or
Radiation therapy (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)
Vaccines, killed virus (because normal defense mechanisms may be suppressed by lomustine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)
» Vaccines, live virus (because normal defense mechanisms may be suppressed by lomustine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the lomustine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members)
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Hepatic function tests (may be elevated transiently and reversibly)
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster (risk of severe generalized disease)
» Infection
» Pulmonary function impairment, especially with a baseline below 70% of the forced vital capacity (FVC) or carbon monoxide diffusion capacity (DL CO){01} (increased risk of pulmonary toxicity {01})
» Renal function impairment
» Sensitivity to lomustine{01}
» Caution should be used also in patients who have had previous cytotoxic drug therapy and radiation therapy.
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Alanine aminotransferase (ALT [SGPT]) values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin values, serum and
Lactate dehydrogenase (LDH) values, serum (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)
» Blood urea nitrogen (BUN) concentrations and
» Creatinine concentrations, serum (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)
» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count (determinations recommended prior to initiation of therapy and at periodic intervals during and after {01} therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)
Pulmonary function tests (recommended prior to initiation of therapy and at periodic intervals during therapy {01})
Side/Adverse Effects
Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Immunosuppression or leukopenia or infection (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—usually asymptomatic
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic
Note: Maximum thrombocytopenia occurs about 4 weeks after a dose and persists for 1 to 2 weeks. Maximum leukopenia occurs about 4 to 6 weeks after a dose and persists for 1 to 2 weeks. Recovery usually occurs within 6 to 7 weeks after administration. Severity of bone marrow depression varies and determines subsequent dosage of lomustine.
Incidence less frequent
Anemia (unusual tiredness or weakness)
neurotoxicity (awkwardness; confusion; slurred speech; unusual tiredness)—not definitely attributed to medication
renal toxicity and failure (decrease in urination; swelling of feet or lower legs)—especially with long-term therapy
stomatitis (sores in mouth and on lips)
Incidence rare
Hepatotoxicity{01} —usually asymptomatic
pulmonary infiltrates and/or fibrosis (cough; shortness of breath)
Note: Pulmonary toxicity has occurred after cumulative doses ranging from 600 to 1240 mg or therapy of 6 months or more.
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Loss of appetite
nausea and vomiting
Note: Loss of appetite may persist for 2 to 3 days after a dose.
Nausea and vomiting occur 3 to 6 hours after a dose and usually persist less than 24 hours.
Incidence less frequent
Darkening of skin
diarrhea
skin rash and itching
Those not indicating need for medical attention
Incidence less frequent
Loss of hair
Those indicating the need for medical attention if they occur after medication is discontinued
Bone marrow depression (black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin; unusual bleeding or bruising)
Note: Cumulative myelosuppression may occur with repeated doses.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Lomustine (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to lomustine
Pregnancy—Use not recommended because of mutagenic, teratogenic, and carcinogenic potential; advisability of using contraception; telling physician immediately if pregnancy is suspected
Breast-feeding—Not recommended because of risk of serious side effects
Other medications, especially other bone marrow depressants or previous cytotoxic drug or radiation therapy
Other medical problems, especially chickenpox, herpes zoster, infection, pulmonary function impairment, or renal function impairment
Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed
Explanation of different kinds of capsules included in one container
Caution in taking combination therapy; taking each medication at the right time
Frequency of nausea and vomiting, which usually lasts less than 24 hours; taking on an empty stomach to reduce nausea
Checking with physician if vomiting occurs shortly after dose is taken
» Proper dosing
Precautions while using this medication
» Importance of close monitoring by the physician
» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth
Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs
» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur
Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done
Not touching eyes or inside of nose unless hands washed immediately before
Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters
Avoiding contact sports or other situations where bruising or injury could occur
Side/adverse effects
May cause adverse effects such as blood problems, loss of hair, and cancer; importance of discussing possible effects with physician
Signs of potential side effects, especially immunosuppression, leukopenia, infection, thrombocytopenia, anemia, neurotoxicity, renal toxicity, stomatitis, hepatotoxicity, and pulmonary infiltrates and/or fibrosis
Physician or nurse can help in dealing with side effects
General Dosing Information
Patients receiving lomustine should be under supervision of a physician experienced in cancer chemotherapy.
A variety of dosage schedules and regimens of lomustine, alone or in combination with other antitumor agents, are used. The prescriber may consult the medical literature as well as the manufacturer's literature in choosing a specific dosage.
Treatment with lomustine is continued as long as the medication is effective. If no response occurs after 1 or 2 courses, a response is unlikely.
Some cross-resistance has been reported between lomustine and carmustine.
Frequency and duration of nausea and vomiting may be reduced in some patients by administration of antiemetics prior to dosing and by administration of lomustine to fasting patients.
Dosage subsequent to the initial dose should be adjusted to meet the individual requirements of each patient based on the hematological response of the patient to the previous dose. An additional course of lomustine should be given only after circulating blood elements have returned to acceptable levels (leukocytes above 4000 per cubic millimeter and platelets above 100,000 per cubic millimeter).
Because of the delayed and cumulative bone marrow suppression caused by lomustine, the medication should be given no more frequently than every 6 weeks.
Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of lomustine. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and any aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.
Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.
Combination chemotherapy
Lomustine may be used in combination with other agents in various regimens. As a result, incidence and/or severity of side effects may be altered and different dosages (usually reduced) may be used. For example, lomustine is part of the following chemotherapeutic combinations (some commonly used acronyms are in parentheses): —lomustine, doxorubicin, and vinblastine (CAVE).
—cyclophosphamide, methotrexate, and lomustine (CMC).
For specific dosages and schedules, consult the literature. For information regarding each agent, consult the individual monographs.
Oral Dosage Forms
Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.
LOMUSTINE CAPSULES
Usual adult and adolescent dose
Tumors, brain, primary or
[Carcinoma, colorectal]1 or
[Carcinoma, lung, non-small cell] or
[ Carcinoma, breast] or
Lymphomas, Hodgkin's or
[ Multiple myeloma]1 or
[Melanoma, malignant]
Initial: As a single agent—Oral, 100 to 130 mg per square meter of body surface area as a single dose, repeated every six weeks. A lower dose is used when lomustine is combined with other agents.
Note: In patients with suppressed bone marrow function, dosage is reduced to 100 mg per square meter of body surface area as a single dose, repeated every six weeks.
A suggested dosage adjustment schedule for subsequent doses is:
| Nadir after Prior Dose (cells per cubic millimeter) |
% of Prior Dose To Be Given |
|
|---|---|---|
| Leukocytes |
Platelets |
|
| >4000 |
>100,000 |
100 |
| 3000–3999 |
75,000–99,999 |
100 |
| 2000–2999 |
25,000–74,999 |
70 |
| <2000 |
<25,000 |
50 |
Usual pediatric dose
See Usual adult and adolescent dose.
Strength(s) usually available
U.S.—
10 mg (Rx) [CeeNU (mannitol)]
40 mg (Rx) [CeeNU (mannitol)]
100 mg (Rx) [CeeNU (mannitol)]
Note: Available only in a dose pack that contains a total of 300 mg (2 capsules of each strength) and provides enough medication for titration of a single dose. The total prescribed dose, to within 10 mg, can be obtained using the appropriate combination of capsules. {01}
Canada—
10 mg (Rx) [CeeNU (mannitol)]
40 mg (Rx) [CeeNU (mannitol)]
100 mg (Rx) [CeeNU (mannitol)]
Note: Available also in a dose pack that contains a total of 300 mg (2 capsules of each strength) and will provide enough medication for titration of a single dose. The total prescribed dose, to within 10 mg, can be obtained using the appropriate combination of capsules. {02}
Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.
Auxiliary labeling:
• There may be two or more different types of capsules in this container. This is not an error. It is important that you take all of the capsules so that you receive the right dose of the medicine.
• Take on an empty stomach.
Note: A patient information label should be attached, explaining the difference in appearance of the capsules and advising the patient that all of the capsules together constitute one dose.
No more than one dose should be dispensed at a time and refills supplied only after direct verbal or written order by the physician.
Revised: 09/30/1997
References
Note: References used in the development and subsequent revisions of this monograph have not been incorporated into the database and therefore are not listed below.
- CeeNU package insert (Bristol—US), Rev 7/88.
- CeeNU product monograph (Bristol—Canada), Rev 5/91.
- Salmon SE, Cassady JR. Plasma cell neoplasms. In: DeVita VT, Hellman S, Rosenberg SA. Cancer principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997. p. 2358.
- Cohen AM, Minsky BD, Schilsky RL. Cancer of the colon. In: DeVita VT, Hellman S, Rosenberg SA. Cancer principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997. p. 1171.
- Reviewers' responses to Hematologic-Oncologic Disease Advisory Panel Memo #9 of 1/30/97.
