Mercaptopurine

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Side Effects & Adverse Reactions

Mercaptopurine is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient's risk of neoplasia. Cases of hepatosplenic T-cell lymphoma have been reported in patients treated with mercaptopurine for inflammatory bowel disease. The safety and efficacy of mercaptopurine in patients with inflammatory bowel disease have not been established.

Bone Marrow Toxicity
The most consistent, dose-related toxicity is bone marrow suppression. This may be manifest by anemia, leukopenia, thrombocytopenia, or any combination of these. Any of these findings may also reflect progression of the underlying disease. In many patients with severe depression of the formed elements of the blood due to mercaptopurine, the bone marrow appears hypoplastic on aspiration or biopsy, whereas in other cases it may appear normocellular. The qualitative changes in the erythroid elements toward the megaloblastic series, characteristically seen with the folic acid antagonists and some other antimetabolites, are not seen with this drug. Life-threatening infections and bleeding have been observed as a consequence of mercaptopurine-induced granthrombocytopenia and thrombocytopenia. Since mercaptopurine may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an unexpected abnormally large fall in any of the formed elements of the blood, if not attributable to another drug or disease process.
Individuals who are homozygous for an inherited defect in the TPMT (thiopurine-S-methyltransferase) gene are unusually sensitive to the myelosuppressive effects of mercaptopurine and prone to developing rapid bone marrow suppression following the initiation of treatment. Laboratory tests are available, both genotypic and phenotypic, to determine the TPMT status. Substantial dose reductions are generally required for homozygous-TPMT deficiency patients (two non-functional alleles) to avoid the development of life threatening bone marrow suppression. Although heterozygous patients with intermediate TPMT activity may have increased mercaptopurine toxicity, this is variable, and the majority of patients tolerate normal doses of mercaptopurine. If a patient has clinical or laboratory evidence of severe toxicity, particularly myelosuppression, TPMT testing should be considered. In patients who exhibit excessive myelosuppression due to 6-mercaptopurine, it may be possible to adjust the mercaptopurine dose and administer the usual dosage of other myelosuppressive chemotherapy as required for treatment (see DOSAGE AND ADMINISTRATION).
Bone marrow toxicity may be more profound in patients treated with concomitant allopurinol (see PRECAUTIONS: Drug Interactionsand DOSAGE AND ADMINISTRATION). This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalamine, or sulfasalazine.

Hepatotoxicity
Mercaptopurine is hepatotoxic in animals and humans. A small number of deaths have been reported that may have been attributed to hepatic necrosis due to administration of mercaptopurine. Hepatic injury can occur with any dosage, but seems to occur with more frequency when doses of 2.5 mg/kg/day are exceeded. The histologic pattern of mercaptopurine hepatotoxicity includes features of both intrahepatic cholestasis and parenchymal cell necrosis, either of which may predominate. It is not clear how much of the hepatic damage is due to direct toxicity from the drug and how much may be due to a hypersensitivity reaction. In some patients jaundice has cleared following withdrawal of mercaptopurine and reappeared with its reintroduction.
Published reports have cited widely varying incidences of overt hepatotoxicity. In a large series of patients with various neoplastic diseases, mercaptopurine was administered orally in doses ranging from 2.5 mg/kg to 5.0 mg/kg without evidence of hepatotoxicity. It was noted by the authors that no definite clinical evidence of liver damage could be ascribed to the drug, although an occasional case of serum hepatitis did occur in patients receiving 6-MP who previously had transfusions. In reports of smaller cohorts of adult and pediatric leukemic patients, the incidence of hepatotoxicity ranged from 0% to 6%. In an isolated report by Einhorn and Davidsohn, jaundice was observed more frequently (40%), especially when doses exceeded 2.5 mg/kg. Usually, clinically detectable jaundice appears early in the course of treatment (1 to 2 months). However, jaundice has been reported as early as 1 week and as late as 8 years after the start of treatment with mercaptopurine. The hepatotoxicity has been associated in some cases with anorexia, diarrhea, jaundice and ascites. Hepatic encephalopathy has occurred.
Monitoring of serum transaminase levels, alkaline phosphatase, and bilirubin levels may allow early detection of hepatotoxicity. It is advisable to monitor these liver function tests at weekly intervals when first beginning therapy and at monthly intervals thereafter. Liver function tests may be advisable more frequently in patients who are receiving mercaptopurine with other hepatotoxic drugs or with known pre-existing liver disease. The onset of clinical jaundice, hepatomegaly, or anorexia with tenderness in the right hypochondriuim are immediate indications for withholding mercaptopurine until the exact etiology can be identified. Likewise, any evidence of deterioration in liver function studies, toxic hepatitis, or biliary stasis should prompt discontinuation of the drug and a search for an etiology of the hepatotoxicity.
The concomitant administration of mercaptopurine with other hepatotoxic agents requires especially careful clinical and biochemical monitoring of hepatic function. Combination therapy involving mercaptopurine with other drugs not felt to be hepatotoxic should nevertheless be approached with caution. The combination of mercaptopurine with doxorubicin was reported to be hepatotoxic in 19 of 20 patients undergoing remission-induction therapy for leukemia resistant to previous therapy.

Immunosuppression

Pregnancy

Pregnancy Category D

There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

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Legal Issues

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FDA Safety Alerts

There are currently no FDA safety alerts available for this drug.

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Manufacturer Warnings

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FDA Labeling Changes

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Uses

Mercaptopurine is indicated for maintenance therapy of acute lymphatic (lymphocytic, lymophoblastic) leukemia as part of a combination regimen. The response to this agent depends upon the particular subclassification of acute lymphatic leukemia and the age of the patient (pediatric or adult).
Mercaptopurine is not effective prophylaxis or treatment of central nervous system leukemia.
Mercaptopurine is not effective in acute myelogenous leukemia, chronic lymphatic leukemia, the lymphomas (including Hodgkins Disease), or solid tumors.

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History

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Other Information

Mercaptopurine was synthesized and developed by Hitchings, Elion, and associates at the Wellcome Research Laboratories.
Mercaptopurine, known chemically as 6H-purine-6-thione, 1,7-dihydro-, monohydrate, is an analogue of the purine bases adenine and hypoxanthine. Its structural formula is:

Mercaptopurine is available in tablet form for oral administration. Each scored tablet contains 50 mg mercaptopurine and the inactive ingredients corn starch, hypromellose, lactose (anhydrous), lactose (monohydrate), magnesium stearate, potato starch, sodium starch glycolate, and stearic acid.
Each tablet meets the requirements of Test 2 for Dissolution in the USP monograph for Mercaptopurine Tablets, USP.

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Mercaptopurine Manufacturers

Remedyrepack Inc.

Mercaptopurine | Remedyrepack Inc.

Maintenance Therapy
Once a complete hematologic remission is obtained, maintenance therapy is considered essential. Maintenance doses will vary from patient to patient. The usual daily maintenance dose of Mercaptopurine Tablets is 1.5 to 2.5 mg/kg/day as a single dose. It is to be emphasized that in pediatric patients with acute lymphatic leukemia in remission, superior results have been obtained when Mercaptopurine Tablets have been combined with other agents (most frequently with methotrexate) for remission maintenance. Mercaptopurine Tablets should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Dosage with concomitant Allopurinol
When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one-third to one-quarter of the usual dose to avoid severe toxicity.

Dosage in TPMT-deficient Patients
Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe mercaptopurine toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established (see CLINICAL PHARMACOLOGY, WARNINGSand PRECAUTIONSsections).
Most patients with heterozygous TPMT deficiency tolerated recommended mercaptopurine doses, but some required dose reduction. Genotypic and phenotypic testing of TPMT status are available (see CLINICAL PHARMACOLOGY, WARNINGSand PRECAUTIONSsections).

Dosage in Renal and Hepatic Impairment
It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a greater cumulative effect. Consideration should be given to reducing the dosage in patients with impaired hepatic function.

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Teva Pharmaceuticals Usa Inc

Mercaptopurine | Teva Pharmaceuticals Usa Inc

Maintenance Therapy
Once a complete hematologic remission is obtained, maintenance therapy is considered essential. Maintenance doses will vary from patient to patient. The usual daily maintenance dose of mercaptopurine is 1.5 to 2.5 mg/kg/day as a single dose. It is to be emphasized that in pediatric patients with acute lymphatic leukemia in remission, superior results have been obtained when mercaptopurine has been combined with other agents (most frequently with methotrexate) for remission maintenance. Mercaptopurine should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Dosage with Concomitant Allopurinol
When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one third to one quarter of the usual dose to avoid severe toxicity.
Dosage in TPMT-deficient Patients
Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe mercaptopurine toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established. (See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS sections.)

Most patients with heterozygous TPMT deficiency tolerated recommended mercaptopurine doses, but some require dose reduction. Genotypic and phenotypic testing of TPMT status are available. (See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS sections.)
Dosage in Renal and Hepatic Impairment
It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a greater cumulative effect. Consideration should be given to reducing the dosage in patients with impaired hepatic function.

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Par Pharmaceutical Companies, Inc.

Mercaptopurine | Par Pharmaceutical Inc.

Maintenance Therapy: Once a complete hematologic remission is obtained, maintenance therapy is considered essential. Maintenance doses will vary from patient to patient. The usual daily maintenance dose of mercaptopurine is 1.5 to 2.5 mg/kg/day as a single dose. It is to be emphasized that in pediatric patients with acute lymphatic leukemia in remission, superior results have been obtained when mercaptopurine has been combined with other agents (most frequently with methotrexate) for remission maintenance. Mercaptopurine should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-8

There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Dosage with Concomitant Allopurinol: When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one third to one quarter of the usual dose to avoid severe toxicity.

Dosage in TPMT-deficient Patients: Patients with inherited little or no thiopurine-S-methyltransferase (TPMT) activity are at increased risk for severe mercaptopurine toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections).

Most patients with heterozygous TPMT deficiency tolerated recommended mercaptopurine doses, but some require dose reduction. Genotypic and phenotypic testing of TPMT status are available. (See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS sections.)

Dosage in Renal and Hepatic Impairment: It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a greater cumulative effect. Consideration should be given to reducing the dosage in patients with impaired hepatic function.

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Physicians Total Care, Inc.

Mercaptopurine | Physicians Total Care, Inc.

Maintenance Therapy: Once a complete hematologic remission is obtained, maintenance therapy is considered essential. Maintenance doses will vary from patient to patient. The usual daily maintenance dose of mercaptopurine is 1.5 to 2.5 mg/kg/day as a single dose. It is to be emphasized that in pediatric patients with acute lymphatic leukemia in remission, superior results have been obtained when mercaptopurine has been combined with other agents (most frequently with methotrexate) for remission maintenance. Mercaptopurine should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-8

There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Dosage with Concomitant Allopurinol: When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one third to one quarter of the usual dose to avoid severe toxicity.

Dosage in TPMT-deficient Patients: Patients with inherited little or no thiopurine-S-methyltransferase (TPMT) activity are at increased risk for severe mercaptopurine toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections).

Most patients with heterozygous TPMT deficiency tolerated recommended mercaptopurine doses, but some require dose reduction. Genotypic and phenotypic testing of TPMT status are available. (See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS sections.)

Dosage in Renal and Hepatic Impairment: It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a greater cumulative effect. Consideration should be given to reducing the dosage in patients with impaired hepatic function.

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American Health Packaging

Mercaptopurine | American Health Packaging

Maintenance Therapy: Once a complete hematologic remission is obtained, maintenance therapy is considered essential. Maintenance doses will vary from patient to patient. The usual daily maintenance dose of mercaptopurine is 1.5 to 2.5 mg/kg/day as a single dose. It is to be emphasized that in pediatric patients with acute lymphatic leukemia in remission, superior results have been obtained when mercaptopurine has been combined with other agents (most frequently with methotrexate) for remission maintenance. Mercaptopurine should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-8

There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Dosage with Concomitant Allopurinol: When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one third to one quarter of the usual dose to avoid severe toxicity.

Dosage in TPMT-deficient Patients: Patients with inherited little or no thiopurine-S-methyltransferase (TPMT) activity are at increased risk for severe mercaptopurine toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections).

Most patients with heterozygous TPMT deficiency tolerated recommended mercaptopurine doses, but some require dose reduction. Genotypic and phenotypic testing of TPMT status are available. (See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS sections.)

Dosage in Renal and Hepatic Impairment: It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a greater cumulative effect. Consideration should be given to reducing the dosage in patients with impaired hepatic function.

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Roxane Laboratories, Inc

Mercaptopurine | Roxane Laboratories, Inc

Maintenance Therapy
Once a complete hematologic remission is obtained, maintenance therapy is considered essential. Maintenance doses will vary from patient to patient. The usual daily maintenance dose of Mercaptopurine Tablets is 1.5 to 2.5 mg/kg/day as a single dose. It is to be emphasized that in pediatric patients with acute lymphatic leukemia in remission, superior results have been obtained when Mercaptopurine Tablets have been combined with other agents (most frequently with methotrexate) for remission maintenance. Mercaptopurine Tablets should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Dosage with concomitant Allopurinol
When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one-third to one-quarter of the usual dose to avoid severe toxicity.
Dosage in TPMT-deficient Patients
Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe mercaptopurine toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections).

Most patients with heterozygous TPMT deficiency tolerated recommended mercaptopurine doses, but some required dose reduction. Genotypic and phenotypic testing of TPMT status are available (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections).
Dosage in Renal and Hepatic Impairment
It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a greater cumulative effect. Consideration should be given to reducing the dosage in patients with impaired hepatic function.

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Mylan Pharmaceuticals Inc.

Mercaptopurine | Steriweb Medical, Llc

adults and children 2 years and older: clean the affected area; apply a small amount on the area 1-3 times daily; may be covered with a sterile bandage (let dry first) children under 2 years: ask a doctor

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