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Mercaptopurine (Systemic)


VA CLASSIFICATION
Primary: AN300
Secondary: IM403; MS103; GA900

Commonly used brand name(s): Purinethol.

Another commonly used name is
6-MP .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

immunosuppressant—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Leukemia, acute lymphocytic (treatment) or
Leukemia, acute nonlymphocytic (treatment)—Mercaptopurine is indicated for remission induction and maintenance therapy of acute lymphocytic and acute nonlymphocytic leukemia {01}.

[Leukemia, chronic myelocytic (treatment)]—Mercaptopurine is indicated for treatment of chronic myelocytic leukemia {02}.

[Lymphomas, non-Hodgkin's (treatment) ]1—Mercaptopurine is indicated for treatment of some pediatric non-Hodgkin's lymphomas {03}.

[Bowel disease, inflammatory (treatment) ]1—Mercaptopurine is also used in the treatment of regional enteritis (Crohn's disease) and ulcerative colitis.

[Arthritis, psoriatic (treatment) ]1—Mercaptopurine is used in the treatment of selected cases of severe psoriatic arthritis.

—Extreme caution is recommended in use of mercaptopurine for non-neoplastic conditions because of potential carcinogenicity with long-term use of this agent.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    170.19

pKa—
    7.6

Mechanism of action/Effect:

Mercaptopurine is an antimetabolite of the purine analog type. Mercaptopurine is cell cycle–specific for the S phase of cell division. Activity occurs as the result of activation in the tissues and may include inhibition of DNA synthesis with a lesser effect on RNA synthesis.

Absorption:

Variably and incompletely (up to 50%) absorbed from the gastrointestinal tract.

Distribution:

Crosses the blood-brain barrier, but in insufficient amounts to treat meningeal leukemia.

Protein binding:

Low (20%).

Biotransformation:

Hepatic (activation and catabolism); degradation primarily by xanthine oxidase.

Half-life:

Triphasic—45 minutes, 2.5 hours, and 10 hours.

Elimination:
    Renal (7 to 39% unchanged).
    In dialysis—Removable by dialysis.


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.

Antimetabolites have been shown to be carcinogenic in animals and may be associated with an increased risk of development of secondary carcinomas in humans, although the risk appears to be less than with alkylating agents.

Mercaptopurine causes chromosome abnormalities in animals and humans and dominant-lethal mutations in male mice.

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—
Mercaptopurine is not recommended during pregnancy {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.

Mercaptopurine is embryopathic in rats and has been associated with an increased risk of abortion or premature births in humans; the risk of teratogenicity in surviving offspring has not been studied.

FDA Pregnancy Category D.

Breast-feeding

Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended while mercaptopurine is being administered because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity). It is not known whether mercaptopurine is distributed into breast milk {01}.

Pediatrics

Appropriate studies on the relationship of age to the effects of mercaptopurine 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 mercaptopurine in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require dosage reduction in patients receiving mercaptopurine.


Dental

The bone marrow depressant effects of mercaptopurine 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.

Mercaptopurine 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):


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    (concurrent use with allopurinol may result in greatly increased mercaptopurine activity and toxicity because of inhibition of metabolism; careful monitoring is recommended. It is recommended that mercaptopurine dosage be reduced to one-third to one-fourth of the usual dosage in patients receiving 300 to 600 mg of allopurinol a day concurrently to reduce or prevent hyperuricemia or to slow the metabolism of mercaptopurine. In addition, mercaptopurine may raise the concentration of blood uric acid; dosage adjustment of antigout agents may be necessary to control hyperuricemia and gout; concurrent use of uricosuric antigout agents should be avoided because of the risk of uric acid nephropathy)


Anticoagulants, coumarin- or indandione-derivative    (mercaptopurine may increase anticoagulant activity and/or increase the risk of hemorrhage as a result of decreased hepatic synthesis of procoagulant factors and interference with platelet formation or may reduce anticoagulant activity by means of increased prothrombin synthesis or activation)


Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of mercaptopurine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of mercaptopurine, 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)


» Hepatotoxic medications, other (see Appendix II )    (concurrent use may increase the risk of hepatotoxicity and should be avoided )


» Immunosuppressants, other, such as:
Azathioprine
Chlorambucil
Corticosteroids, glucocorticoid
Corticotropin (ACTH)
Cyclophosphamide
Cyclosporine
Muromonab-CD3    (concurrent use with mercaptopurine may increase the risk of infection and development of neoplasms)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by mercaptopurine 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 mercaptopurine 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 mercaptopurine 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 diagnostic test results
Glucose and
Uric acid    (serum concentrations may be falsely increased when the sequential multiple analyzer [SMA] is used)

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
» 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    (lower dosage recommended)


» Infection
» Renal function impairment    (lower dosage recommended)


Sensitivity to mercaptopurine
» Caution should be used also in patients who have had previous cytotoxic drug therapy and 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):
» Alanine aminotransferase (ALT [SGPT]) values, serum and
» Aspartate aminotransferase (AST [SGOT]) values, serum and
» Bilirubin concentrations, 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 therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


Uric acid 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)


Note: In patients with acute leukemia and high total leukocyte counts, a rapid fall in leukocyte count may occur with mercaptopurine therapy. Daily blood counts are recommended in these patients.




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
    
Anemia (unusual tiredness or weakness)
    
hepatotoxicity or biliary stasis (yellow eyes or skin)
    
immunosuppression, 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: Anemia occurs with high doses.
Leukopenia and thrombocytopenia (usually mild) may begin 5 to 6 days after initiation of therapy and persist about 7 days after withdrawal.


Incidence less frequent
    
Hyperuricemia or uric acid nephropathy (joint pain; lower back or side pain; swelling of feet or lower legs)
    
loss of appetite or nausea and vomiting

Note: Hyperuricemia and uric acid nephropathy occur 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.
Crystals of mercaptopurine have been found in urine of children receiving high dosage (1000 mg per square meter of body surface daily).
Loss of appetite or nausea and vomiting may be symptoms of overdosage.


Incidence rare
    
Gastrointestinal ulceration (black, tarry stools; stomach pain)
    
stomatitis (sores in mouth and on lips)

Note: Stomatitis is common with large doses.




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Darkening of skin
    
diarrhea
    
headache
    
skin rash and itching
    
weakness



Those indicating 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)
    
hepatotoxicity (yellow eyes or skin)




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Mercaptopurine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
  Conditions affecting use, especially:
Sensitivity to mercaptopurine

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 allopurinol, other bone marrow depressants, other hepatotoxic medications, other immunosuppressants, probenecid, sulfinpyrazone, or previous cytotoxic drug or radiation therapy
Other medical problems, especially chickenpox, herpes zoster, hepatic function impairment, infection, or renal function impairment

Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed

Caution in taking combination therapy; taking each medication at the right time

Importance of ample fluid intake and subsequent increase in urine output to aid in excretion of uric acid

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

» Possibility of increased toxicity if alcohol is ingested

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding 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
Caution if any laboratory tests required; possible interference with serum glucose and uric acid values measured by sequential multiple analyzer (SMA)


Side/adverse effects
Importance of discussing possible effects, including cancer, with physician

Signs of potential side effects, especially anemia, hepatotoxicity, biliary stasis, immunosuppression, leukopenia, infection, thrombocytopenia, hyperuricemia, uric acid nephropathy, loss of appetite, nausea and vomiting, gastrointestinal ulceration, and stomatitis

Physician or nurse can help in dealing with side effects


General Dosing Information
Patients receiving mercaptopurine should be under supervision of a physician experienced in immunosuppressive and antimetabolite chemotherapy.

A variety of dosage schedules and regimens of mercaptopurine, 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.

Dosage must be adjusted to meet the individual requirements of each patient, based on clinical response and appearance or severity of toxicity.

Development of uric acid nephropathy in patients with leukemia or lymphoma may be prevented by adequate oral hydration. Alkalinization of urine may be necessary if serum uric acid concentrations are elevated. Allopurinol should be administered with caution and only if uric acid concentrations are unacceptably high.

It is recommended that mercaptopurine dosage be reduced to one-third to one-fourth of the usual dosage in patients receiving 300 to 600 mg of allopurinol a day concurrently to reduce or prevent hyperuricemia or to slow the metabolism of mercaptopurine.

Because the actions of mercaptopurine may be delayed, it is recommended that mercaptopurine therapy be discontinued promptly at the first sign of marked leukopenia (particularly granulocytopenia) or thrombocytopenia, hemorrhage or bleeding tendencies, or jaundice. Therapy may be resumed at one-half the previous dosage when the leukocyte count remains constant for 2 or 3 days, or rises.

In acute leukemia, mercaptopurine may be administered despite the presence of thrombocytopenia and bleeding; stoppage of bleeding and increase in platelet count have occurred during treatment in some cases and platelet transfusions may be useful in others.

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of mercaptopurine. 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 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
Mercaptopurine 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.


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.

MERCAPTOPURINE TABLETS USP

Usual adult dose
Leukemia, acute lymphocytic or
Leukemia, acute nonlymphocytic
Initial: Oral, 2.5 mg per kg of body weight or 80 to 100 mg per square meter of body surface area (to the nearest 25 mg) a day in single or divided doses. If there is no clinical improvement and no leukocyte depression after four weeks at this dosage, an increase in dosage to 5 mg per kg of body weight a day may be attempted.

Maintenance: Oral, 1.5 to 2.5 mg per kg of body weight or 50 to 100 mg per square meter of body surface area a day.

[Inflammatory bowel disease]1
Oral, 1.5 mg per kg of body weight per day, the dosage being adjusted as necessary. If there is no clinical improvement and no leukocyte depression after two to three months at this dosage, a gradual increase in dosage to 2.5 mg per kg of body weight per day may be attempted.


Usual pediatric dose
Leukemia, acute lymphocytic or
Leukemia, acute nonlymphocytic
Oral, 2.5 mg per kg of body weight or 75 mg per square meter of body surface area (to the nearest 25 mg) a day in single or divided doses.


Strength(s) usually available
U.S.—


50 mg (Rx) [Purinethol (scored) (lactose)]

Canada—


50 mg (Rx) [Purinethol (scored)]

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 well-closed container.



Revised: 05/22/2002



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.

  1. Purinethol product information (BW—US), In: PDR Physicians' desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989.
  1. Purinethol product monograph (Glaxo Wellcome—Canada), Rev 1/97.
  1. Childhood non-Hodgkin's lymphoma. National Cancer Institute. Available from: URL: http://cancernet.nci.nih.gov
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