Uracil Mustard (Systemic)
VA CLASSIFICATION
Primary: AN100
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
†Not commercially available in Canada.
Category:
Antineoplastic—
Indications
Accepted
Uracil mustard has been used for the following indications, although use has generally been replaced by that of more effective agents:— —for palliative treatment of chronic lymphocytic and myelocytic leukemia.
—for palliative treatment of non-Hodgkin's lymphomas of the histiocytic or lymphocytic type.
—for palliative treatment of mycosis fungoides.
—for palliative treatment of the early stages of polycythemia vera before the development of leukemia or myelofibrosis.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
252.10
Mechanism of action/Effect:
Uracil mustard is an alkylating agent of the nitrogen mustard type. Uracil mustard is a bifunctional alkylating agent, and is cell cycle–phase nonspecific. Activity occurs as a result of formation of an unstable ethylenimmonium ion. Uracil mustard interferes with the function of DNA and RNA and is also capable of cross-linking DNA.
Elimination:
Renal.
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.
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.
Pregnancy—
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.
Breast-feeding
Although very little information is available regarding excretion of antineoplastic agents in breast milk, breast-feeding is not recommended while uracil mustard is being administered because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).
Pediatrics
Appropriate studies with uracil mustard have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the use of this medication in children are not expected.
Geriatrics
No geriatrics-specific information is available on the use of uracil mustard in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving uracil mustard {02}.
Dental
The bone marrow depressant effects of uracil mustard 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.
Uracil mustard may also rarely cause stomatitis 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):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Allopurinol or
Colchicine or
» Probenecid or
» Sulfinpyrazone (uracil mustard may raise the concentration of blood uric acid; dosage adjustment of antigout agents may be necessary to control hyperuricemia and gout; allopurinol may be preferred to prevent or reverse uracil mustard–induced hyperuricemia because of risk of uric acid nephropathy with uricosuric antigout agents)
Blood dyscrasia–causing medications (See Appendix II ) (leukopenic and/or thrombocytopenic effects of uracil mustard may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of uracil mustard, 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 uracil mustard 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 uracil mustard 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 uracil mustard 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. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. 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
Uric acid concentrations in blood and urine (may be increased)
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 (use of uracil mustard is contraindicated in patients with marked bone marrow depression)
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster (risk of severe generalized disease)
» Gout, history of or
Urate renal stones, history of (risk of hyperuricemia)
» Hepatic function impairment
» Infection
» Renal function impairment
Sensitivity to uracil mustard{03}
» Tumor cell infiltration of bone marrow
» Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy.
Patient monitoring
The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Blood urea nitrogen (BUN) concentrations and
Serum creatinine concentrations (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
» Platelet count and
» Total and, if appropriate, differential leukocyte count (determinations 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)
Serum alanine aminotransferase (ALT [SGPT]) concentrations and
Serum aspartate aminotransferase (AST [SGOT]) concentrations and
Serum bilirubin concentrations and
Serum lactate dehydrogenase (LDH) concentrations (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)
Serum uric acid concentrations (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)
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
Leukopenia or immunosuppression (usually asymptomatic; less frequently, fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)
thrombocytopenia (usually asymptomatic; less frequently, unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)
Note: Maximum bone marrow depression may not occur until 2 to 4 weeks after the medication has been discontinued.
Incidence less frequent
Hyperuricemia or uric acid nephropathy (joint pain; lower back or side pain; swelling of feet or lower legs)
Note: Hyperuricemia or uric acid nephropathy occurs most commonly during initial treatment of patients with leukemia or lymphoma, as a result of rapid cell breakdown, which leads to elevated serum uric acid concentrations.
Incidence rare
Hepatotoxicity (yellow eyes or skin)
stomatitis (sores in mouth and on lips)
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent, dose-related
Diarrhea
nausea or vomiting
Incidence less frequent
Darkening of the skin
irritability
mental depression
nervousness
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, Uracil Mustard (Systemic).
Consider advising the patient on the following (» = major clinical significance):
Before using this medication
Conditions affecting use, especially:
Pregnancy—Advisability of using contraception; telling physician immediately if pregnancy is suspected
See also Precautions to Consider .
Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed
Importance of ample fluid intake and subsequent increase in urine output to aid in excretion of uric acid
» Frequency of nausea and vomiting; importance of continuing medication despite stomach upset
Checking with physician if vomiting occurs shortly after dose is taken
» Proper dosing
Missed dose: Not taking at all; not doubling doses
» Proper storage
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 bacterial 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 occur
» 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 and loss of hair; importance of discussing possible effects with physician
Signs of potential side effects, especially leukopenia, thrombocytopenia, hyperuricemia, uric acid nephropathy, hepatotoxicity, and stomatitis
Physician or nurse can help in dealing with side effects
Possibility of hair loss; should return after treatment has ended
General Dosing Information
Patients receiving uracil mustard should be under supervision of a physician experienced in cancer chemotherapy.
Dosage must be adjusted to meet the individual requirements of each patient, based on clinical response and degree of bone marrow depression.
A variety of dosage schedules and regimens of uracil mustard, 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.
Development of uric acid nephropathy in patients with leukemia or lymphoma may be prevented by adequate oral hydration and, in some cases, administration of allopurinol. Alkalinization of urine may be necessary if serum uric acid concentrations are elevated.
In the absence of bone marrow depression, uracil mustard should be given for at least 3 months before it is considered ineffective.
Although it is not necessary to discontinue uracil mustard following the initial decrease in blood counts, it must be remembered that a dosage approaching or exceeding a total of 1 mg per kg of body weight (mg/kg) for the course may cause irreversible bone marrow damage. It is recommended that uracil mustard therapy be discontinued or dosage reduced at the first sign of a sudden large decrease in leukocyte (particularly granulocyte) or platelet count to prevent irreversible bone marrow depression. Therapy may be resumed when blood counts recover.
Because of the risk of enhanced bone marrow toxicity, an interval of at least 2 to 3 weeks is recommended before starting uracil mustard therapy after a patient has received the maximum effect from radiation or chemotherapy with medications that depress bone marrow function. Recovery from the maximum effect is indicated by a rising leukocyte count, although some clinicians prefer not to administer uracil mustard until the leukocyte count returns to normal.
Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of uracil mustard. 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.
Oral Dosage Forms
URACIL MUSTARD CAPSULES USP
Note: Uracil mustard capsules are not commercially available in Canada.
Usual adult dose
Oral, 150 mcg (0.15 mg) per kg of body weight once a week for four weeks.
Usual adult prescribing limits
Total dosage of 1 mg per kg of body weight or greater sharply increases the risk of irreversible bone marrow depression.
Usual pediatric dose
Oral, 300 mcg (0.3 mg) per kg of body weight once a week for four weeks.
Strength(s) usually available
U.S.—
1 mg (Rx)[Generic](tartrazine)(lactose)
Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.
Revised: 06/03/1994
References
Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.
- General concept per Geriatrics Advisory Panel (1985-1990), 1990 revision.
- General precaution per DID policy, 1990 revision.
