Mercaptopurine

— THERAPEUTIC CATEGORIES —
  • Leukemias, lymphomas, and other hematologic cancers
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Mercaptopurine Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Mercaptopurine (6-MP) 50mg; scored tabs.

    Pharmacological Class

    Antimetabolite.

    How Supplied

    Contact supplier

    Storage

    Store at 20°C to 25°C (68°F to 77°F).

    Manufacturer

    Various generic manufacturers

    Mercaptopurine Indications

    Indications

    Maintenance therapy of acute lymphatic leukemia as part of a combination regimen.

    Mercaptopurine Dosage and Administration

    Prior to Treatment Evaluations

    Verify pregnancy status in females of reproductive potential prior to initiating.

    Adults and Children

    Individualize. Usual range: 1.5–2.5mg/kg/day as a single dose. Concomitant allopurinol: reduce mercaptopurine to ⅓–¼ of the usual dose. TPMT- or NUDT15-deficient, renal or hepatic impairment: reduce dose (see full labeling).

    Adults and Children

    The recommended starting dosage of mercaptopurine tablets is 1.5mg/kg to 2.5mg/kg orally once daily as part of combination chemotherapy maintenance regimen. Take consistently with or without food. 

    Monitor CBC and adjust dose to maintain absolute neutrophil count (ANC) at a desirable level and for excessive myelosuppression. Evaluate the bone marrow in patients with prolonged myelosuppression or repeated episodes of myelosuppression to assess leukemia status and marrow cellularity.

    Patients with severe myelosuppression or repeated episodes of myelosuppression: Evaluate thiopurine S-methyltransferase (TPMT) and nucleotide diphosphatase (NUDT15) status.

    Missed dose: continue with the next scheduled dose.

    Renal Impairment

    For patients with renal impairment (CrCl<50mL/min), use the lowest recommended starting dosage or increase the dosing interval to every 36 to 48 hours. Adjust based on ANC and adverse reactions.

    Hepatic Impairment

    For patients with hepatic impairment, use the lowest recommended starting dosage and adjust based on ANC and adverse reactions.

    Other Modifications

    Males with female partners of reproductive age: use effective contraception during treatment and for 3 months after the last dose.

    Dose reduction may be required for patients with heterozygous or homozygous TPMT or NUDT15 deficiency. Consider all clinical information when interpreting results from phenotypic testing used to determine the level of thiopurine nucleotides or TPMT activity in erythrocytes, since some coadministered drugs can influence measurement of TPMT activity in blood and blood from recent transfusions will misrepresent a patient’s actual TPMT activity.

    Mercaptopurine Contraindications

    Contraindications

    Prior resistance to mercaptopurine.

    Mercaptopurine Boxed Warnings

    Not Applicable

    Mercaptopurine Warnings/Precautions

    Warnings/Precautions

    Not effective in CNS leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, the lymphomas (including Hodgkin's disease), or solid tumors. Myelosuppression; monitor CBCs weekly and adjust dose for severe cytopenias. Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities or repeated myelosuppression. Monitor serum transaminase, alkaline phosphatase, and bilirubin levels at weekly intervals when starting therapy, then monthly thereafter; interrupt treatment if evidence of hepatotoxicity occurs. Concomitant other hepatotoxic drugs or with pre-existing liver disease; monitor LFTs more frequently. Immunosuppression. Inflammatory bowel disease. Renal or hepatic impairment. Elderly. Pregnancy, nursing mothers: not recommended.

    Warnings/Precautions

    Myelosuppression

    • Manifested by anemia, leukopenia, thrombocytopenia, or any combination.
    • Monitor CBC and adjust dosage for excessive myelosuppression.
    • In patients with severe myelosuppression or repeated episodes: Consider testing for TPMT or NUDT15 deficiency.
    • TPMT genotyping or phenotyping (red blood cell TPMT activity) and NUDT15 genotyping can identify patients who have reduced activity of these enzymes.
    • Dose reduction may be required for patients with heterozygous or homozygous TPMT or NUDT15 deficiency.
    • Coadministration with allopurinol, aminosalicylates or other myelosuppressive products may exacerbate myelosuppression.
    • Reduce mercaptopurine dose with coadministered allopurinol.

    Hepatotoxicity

    • Mercaptopurine is hepatotoxic; reportes of death attributed to hepatic necrosis have been reported.
    • Hepatic injury can occur at any dosage but occurs with greater frequency when the recommended dosage is exceeded.
    • Hepatotoxicity has been associated with anorexia, diarrhea, jaundice and ascites; hepatic encephalopathy has also occurred.
    • Jaundice may appear early (1-2 months) and has been reported as early as 1 week and as late as 8 years after starting mercaptopurine.
    • Jaundice has cleared with withdrawal but has reappeared with rechallenge in some patients.
    • Monitor serum transaminase levels, alkaline phosphatase, and bilirubin levels at weekly intervals when first beginning therapy and at monthly intervals thereafter.
    • Monitor liver tests more frequently in patients who are receiving mercaptopurine with other hepatotoxic products or with known pre-existing liver disease. 
    • Withhold mercaptopurine at onset of hepatotoxicity.

    Immunosuppression

    • Mercaptopurine is immunosuppressive and may impair the immune response to infectious agents or vaccines.
    • Response to all vaccines may be diminished and there is a risk of infection with live virus vaccines.
    • Consult immunization guidelines for immunocompromised patients.

    Treatment Related Malignancies

    • May increase the risk of secondary malignancies; hepatosplenic T-cell lymphoma has been reported in IBD patients treated with mercaptopurine (unapproved use).
    • Risk of developing other malignancies such as skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ.
    • Increased risk appears to be related to degree and duration of immunosuppression.
    • Treatment regimens containing multiple immunosuppressants: Use caution as this could lead to lymphoproliferative disorders, including Epstein-Barr virus-associated lymphoproliferative disorders.

    Macrophage Activation Syndrome (MAS)

    • May develop in patients with autoimmune disorders, particularly IBD.
    • MAS may potentially occur when mercaptopurine is given for this unapproved use.
    • If MAS occurs or is suspected, discontinue mercaptopurine; monitor for and treat infections such as EBV and cytomegalovirus as these are known triggers for MAS.

    Effects on Fertility

    • May impair fertility in males and females based on animal studies.
    • Long-term effects on fertility, including reversibility, have not been studied.

    Pregnancy Considerations

    Can cause fetal harm; an increased risk of miscarriage has been reported in women who received mercaptopurine in the first trimester of pregnancy. Miscarriage and stillbirth have been reported in those who received mercaptopurine after the first trimester. 

    Verify pregnancy status prior to initiating treatment with mercaptopurine. Use effective contraception during treatment and for 6 months after the last dose.

    Nursing Mother Considerations

    There are no data on the presence of mercaptopurine or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for 1 week after the last dose.

    Pediatric Considerations

    Use in pediatric patients is supported by evidence from published literature and clinical experience. Symptomatic hypoglycemia has been reported, particularly in patients less than 6 years of age or with low body mass index.

    Geriatric Considerations

    Clinical studies did not include a sufficient number of patients aged 65 years and older to determine whether there is a different response. In general, dosing in elderly patients should be cautious, usually starting at the lower end of the dosing range.

    Renal Impairment Considerations

    For patients with renal impairment (CrCl<50mL/min), use the lowest recommended starting dosage or increase the dosing interval to every 36 to 48 hours. Adjust based on ANC and adverse reactions.

    Hepatic Impairment Considerations

    For patients with hepatic impairment, use the lowest recommended starting dosage and adjust based on ANC and adverse reactions.

    Other Considerations for Specific Populations

    Males with female partners of reproductive age: use effective contraception during treatment and for 3 months after the last dose.

    Dose reduction may be required for patients with heterozygous or homozygous TPMT or NUDT15 deficiency. Consider all clinical information when interpreting results from phenotypic testing used to determine the level of thiopurine nucleotides or TPMT activity in erythrocytes, since some coadministered drugs can influence measurement of TPMT activity in blood and blood from recent transfusions will misrepresent a patient’s actual TPMT activity.

    Mercaptopurine Pharmacokinetics

    Absorption

    Food has been shown to decrease the exposure of mercaptopurine.

    Distribution

    Plasma protein binding averages 19%.

    Metabolism

    Mercaptopurine is inactivated via 2 major pathways: thiol methylation and oxidation.Variability in mercaptopurine metabolism is one of the major causes of interindividual differences in systemic exposure to the drug and its active metabolites.

    Elimination

    Half-life is less than 2 hours following a single oral dose. 

    46% of dose recovered in the urine (as parent drug and metabolites) in the first 24 hours.

    Mercaptopurine Interactions

    Interactions

    Increased risk of bone marrow suppression with allopurinol, aminosalicylate derivatives (eg, olsalazine, mesalazine, sulphasalazine), trimethoprim-sulfamethoxazole. May antagonize warfarin. Caution with concomitant hepatotoxic agents.

    Mercaptopurine Adverse Reactions

    Adverse Reactions

    Myelosuppression, hyperuricemia/hyperuricosuria, GI upset, intestinal ulceration, rash, hyperpigmentation, alopecia, oligospermia; hepatotoxicity, infection, immunosuppression.

    Mercaptopurine Clinical Trials

    See Literature

    Mercaptopurine Note

    Notes

    Formerly known under the brand name Purinethol.

    Mercaptopurine Patient Counseling

    Patient Counseling

    Major adverse reactions may occur, including myelosuppression, hepatotoxicity, and GI toxicity. Advise patients to report fever, sore throat, jaundice, nausea, vomiting, local infection, bleeding from any site, or symptoms suggestive of anemia.

    Females of reproductive potential should report a known or suspected pregnancy as mercaptopurine can cause fetal harm. Effective contraception should be used during treatment and for 6 months after the last dose.

    Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose.

    Nursing mothers should not breastfeed during treatment and for 1 week after the last dose.

    Mercaptopurine may impair fertility in both males and females.

    Risk of photosensitivity: minimize sun exposure.

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