PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Purine Analogs

    DEA CLASS

    Rx

    DESCRIPTION

    Thiopurine antimetabolite
    Indicated for ALL as part of a combination chemotherapy regimen; common off-label use in gastroenterology for Crohn's disease and ulcerative colitis
    Patients with TPMT or NUDT15 deficiency may be at a higher risk for developing toxicity, especially severe myelosuppression

    COMMON BRAND NAMES

    Purinethol, PURIXAN

    HOW SUPPLIED

    Mercaptopurine/Purinethol Oral Tab: 50mg
    PURIXAN Oral Susp: 1mL, 20mg

    DOSAGE & INDICATIONS

    For the treatment of acute lymphocytic leukemia (ALL).
    As remission maintenance for ALL in combination with other agents.
    Oral dosage
    Adults, Adolescents, Children, and Infants

    1.5 to 2.5 mg/kg orally daily in combination with other agents; start mercaptopurine therapy after a complete hematologic remission is achieved. Single-agent mercaptopurine therapy is rarely used as remission maintenance of ALL. Mercaptopurine oral suspension may be dosed as 1.5 to 2.5 mg/kg daily or 50 to 75 mg/m2 daily in combination with multi-agent chemotherapy. Adjust the mercaptopurine dose to maintain desirable blood counts; a dose reduction is necessary in patients who develop severe hematologic toxicity.

    For maintenance treatment of acute myelogenous leukemia (AML)†, in combination with other chemotherapeutic agents.
    Oral dosage
    Adults, Adolescents, Children, and Infants

    Use is not established; however, 50 or 70 mg/m2/day PO as part of a combination chemotherapy regimen has been studied. Three cycles of consolidation followed by 6 cycles of maintenance therapy did not improve 5-year overall survival (OS) (58.4% vs. 52.4%) or disease-free survival (DFS) (30.4% vs. 35.8%) rates compared with 4 cycles of consolidation in 598 acute myelogenous leukemia (AML) patients (age range, 15 to 64 years) who achieved a complete remission following standard induction therapy in a large, randomized study. In the maintenance therapy regimen used in this study, the mercaptopurine dosage was 70 mg/m2/day orally on days 1 to 7 given in cycles 1, 4, and 5 in combination with other chemotherapy agents. In another study, 18 months of maintenance therapy with mercaptopurine 50 mg/m2/day orally and cytarabine resulted in a significantly worse 5-year OS rate compared with no maintenance therapy (58% vs. 81%; p = 0.04) in AML patients less than 20 years of age who had received induction therapy and 2 cycles of consolidation therapy; additionally, the 5-year DFS rate was not significantly different in the 2 treatment arms (50% vs. 60%, respectively).

    For the treatment of chronic myelogenous leukemia (CML)†.
    Oral dosage
    Adults

    Dose is not established; doses of 50 to 200 mg/day PO or 1.5 mg/kg/day PO divided into 2 doses has been studied with no improvement in survival. Mercaptopurine 50 to 200 mg resulted in no hematologic complete responses (CR) in 30 patients with chronic myelogenous leukemia in blast crisis compared with 6 CR (20%) in 30 matched control patients who received treatment with IV chemotherapy in a small study. The median overall survival (OS) times were not significantly different between the 2 treatment arms (4.7 vs. 3.8 months, respectively). In a nonrandomized study in 47 patients with Philadelphia chromosome-positive, chronic phase chronic granulocytic leukemia, mercaptopurine (1.5 mg/kg daily orally in 2 divided doses) plus hydroxyurea (1.5 mg/kg daily orally in 2 divided doses) given until disease progression resulted in a median chronic phase duration of 41 months and a median OS time of 45 months. However, these efficacy parameters were not significantly different for combination therapy compared with hydroxyurea alone in another nonrandomized study in 45 patients.

    For the treatment of Crohn's disease†.
    Oral dosage
    Adults

    0.75 to 1.5 mg/kg/day PO is the usual maximal dose range; doses are usually titrated to target from 25 mg or 50 mg PO once daily, with starting and target (goal) doses based on metabolizer status. Consider TPMT genotyping or enzymatic activity testing prior to initiating therapy. Drug interactions can lead to reduced efficacy or increased toxicity; review drug interactions. The American College of Gastroenterology states that mercaptopurine may be used in treatment of active Crohn's disease. Mercaptopurine alone is not more effective than placebo to induce remission; however, it is effective for maintenance of remission in patients with Crohn's disease. Once remission is induced with corticosteroids, a thiopurine should be considered for use for steroid-sparing. Patients who are steroid dependent should be started on thiopurines with or without anti-TNF therapy. Mercaptopurine. typically at reduced doses, can also be used as adjunctive therapy for reducing immunogenicity against biologic therapy.

    Children and Adolescents 3 years and older

    1 to 1.5 mg/kg/day PO is the usual initial and maximal target (goal) dose range recommended as one option for maintenance of steroid-free remission in children at risk for poor disease outcome. Thiopurines alone are not recommended as induction therapy. Consider TPMT genotyping or enzymatic activity testing prior to initiating therapy, as doses need to be adjusted based on metabolizer status. Drug interactions can lead to reduced efficacy or increased toxicity; review drug interactions.

    For the treatment of ulcerative colitis†.
    Oral dosage
    Adults

    1.5 mg/kg/day PO is the usual target (goal) dose recommended as one option for maintenance treatment. Initially, 25 to 50 mg PO once daily, then titrated to goal therapy, is commonly utilized. Consider TPMT genotyping or enzymatic activity testing prior to initiating therapy, as doses need to be adjusted based on metabolizer status. Review drug interactions. Guidelines support the use of thiopurines for maintenance of remission for patients with moderate to severely active UC following steroid induction.  Guidelines do not recommend thiopurine monotherapy for induction of remission.

    Children and Adolescents 3 years and older


    1 to 1.5 mg/kg/day PO is the usual target (goal) dose range recommended as one option for maintenance treatment. Consider TPMT genotyping or enzymatic activity testing prior to initiating therapy, as doses need to be adjusted based on metabolizer status. Review drug interactions. Thiopurines alone are not recommended as induction therapy. Thiopurines may be somewhat more effective than 5-ASA products for maintaining remission in UC, but considering their safety profile, they should generally be reserved as second-line therapy after 5-ASA has failed. Pediatric patients need close monitoring.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2.5 mg/kg or 75 mg/m2 PO daily.

    Geriatric

    2.5 mg/kg or 75 mg/m2 PO daily.

    Adolescents

    2.5 mg/kg or 75 mg/m2 PO daily.

    Children

    2.5 mg/kg or 75 mg/m2 PO daily.

    Infants

    2.5 mg/kg or 75 mg/m2 PO daily.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Initiate mercaptopurine therapy at the lowest recommended starting dosage in patients with hepatic impairment. Adjust subsequent mercaptopurine doses based on efficacy and toxicity.

    Renal Impairment

    Initiate mercaptopurine therapy at the lowest recommended starting dosage in patients with renal impairment. Adjust subsequent mercaptopurine doses based on efficacy and toxicity. Use the lowest recommended starting dosage or increase the dosing interval to 36 to 48 hours in patients with renal impairment (creatinine clearance less than 50 mL/min).

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 1
    NIOSH (Draft) 2020 List: Table 1
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
    Emetic Risk
    Pediatrics
    Doses 4.2 mg/kg/dose or lower: Low
    Administer routine antiemetic prophylaxis prior to treatment.

    Oral Administration
    Oral Solid Formulations

    Take mercaptopurine tablets orally either consistently with or without with food as a single daily dose.
    Do not administer in patients who cannot swallow tablets or patients weighing less than 17 kg.
    If a dose is missed, skip that dose and take the next dose at the next scheduled time.

    Oral Liquid Formulations

    Take mercaptopurine solution orally either consistently with or without with food as a single daily dose.
    Prior to starting therapy and at each clinic visit, review proper storage, preparation, administration, disposal, and clean-up of accidental spillage with the patient or caregiver; direct patients and caregivers to read the Instruction for Use at each mercaptopurine refill.
    The oral suspension comes with a press-in bottle adapter and 2 oral dispensing syringes (1-mL and 5-mL syringe); instruct patients and caregivers on which syringe to use and how to administer the specific dose.
    Shake well for at least 30 seconds.
    Wash the syringe with warm, soapy, water and rinse well; move the plunger up and down under water several times to make sure the inside of the syringe is clean. The syringe should be completely dry before re-use; store in a hygienic place.
    If a dose is missed, skip that dose and take the next dose at the next scheduled time.
    Use the suspension within 8 weeks of opening; discard any remaining drug after 8 weeks.

    STORAGE

    Purinethol:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    PURIXAN:
    - Do not expose product to temperatures above 77 degrees F
    - Store at room temperature (up to 77 degrees F)
    - Store between 59 to 77 degrees F
    - Store in a dry place
    - Use within 8 weeks of first opening

    CONTRAINDICATIONS / PRECAUTIONS

    Anemia, bone marrow suppression, leukopenia, neutropenia, nucleotide diphosphatase deficiency, requires an experienced clinician, thiopurine methyltransferase (TPMT) deficiency, thrombocytopenia

    Severe bone marrow suppression (e.g., anemia, leukopenia, neutropenia, and thrombocytopenia) may occur with mercaptopurine therapy; therefore, treatment with this agent requires an experienced clinician. Monitor complete blood counts (CBC) weekly during therapy; evaluate the bone marrow in patients with prolonged or repeated marrow suppression to assess leukemia status and marrow cellularity. Adjust the mercaptopurine dose to maintain desirable absolute neutrophil count (ANC) and platelet count. Patients who develop severe or repeated episodes of myelosuppression should be evaluated for thiopurine methyltransferase deficiency (TPMT deficiency) or nucleotide diphosphatase deficiency (NUDT15 deficiency) using TPMT genotyping or phenotyping (red blood cell TPMT activity) and NUDT15 genotyping. A dose adjustment is required in patients with homozygous TPMT or NUDT15 deficiency. Patients with heterozygous TPMT or NUDT15 deficiency may require a dose adjustment based on CBC monitoring; patients who are heterozygous for both TPMT and NUDT15 may require larger dose reductions.

    Hepatic disease, hepatotoxicity

    Hepatotoxicity has been reported with mercaptopurine therapy; fatal cases of hepatic necrosis have occurred. Initiate mercaptopurine at the low end of the dosing range in patients with hepatic impairment. Monitor liver function tests weekly at the start of mercaptopurine therapy and then monthly thereafter; consider more frequent monitoring in patients receiving other hepatotoxic agents or have pre-existing hepatic disease. Hold mercaptopurine therapy in patients who develop signs or symptoms of hepatotoxicity (e.g., jaundice, hepatomegaly, or anorexia with right-side abdominal tenderness). Discontinue therapy for toxic hepatitis or biliary stasis. Doses exceeding 2.5 mg/kg per day may be associated with a greater risk of hepatic injury.  Use the lowest recommended starting dosage in patients with hepatic impairment and adjust the dosage to maintain an absolute neutrophil count at the desired level.

    Renal impairment

    Use mercaptopurine with caution in patients with renal impairment; consider starting therapy at the low end of the dosage range in these patients.  Use the lowest recommended starting dosage or increase the dosing interval to 36 to 48 hours in patients with renal impairment (creatinine clearance less than 50 mL/min); adjust the mercaptopurine dosage to maintain an absolute neutrophil count at the desired level.

    Vaccination

    Due to the potential for a suboptimal antibody response and risk of infection with live virus vaccines, vaccination during mercaptopurine therapy should be avoided.

    Autoimmune disease, immunosuppression, infection, inflammatory bowel disease, new primary malignancy

    Mercaptopurine causes immunosuppression and may increase the risk of infection and/or a new primary malignancy. Cases of hepatosplenic T-cell lymphoma have been reported following mercaptopurine use for the treatment of inflammatory bowel disease (IBD) (unapproved use). Patients who receive mercaptopurine for the treatment of autoimmune disease (e.g., IBD) are at increased risk for developing macrophage activation syndrome (MAS), also known as hemophagocytic lymphohistiocytosis. Monitor patients for infections that may trigger MAS such as Epstein-Barr virus and cytomegalovirus. Discontinue mercaptopurine therapy if MAS is diagnosed or suspected.

    Sunlight (UV) exposure

    Photosensitivity has been reported with mercaptopurine therapy. Patients should be advised to protect themselves from sunlight (UV) exposure (e.g., wear protective clothing, use a broad spectrum UVA/UVB sunscreen, and wear protective lip balm when outdoors).

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) or hyperuricemia/hyperuricosuria may occur with mercaptopurine therapy; consider increased hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase inhibitor to minimize the renal effects of TLS.

    Children, hypoglycemia, infants

    Symptomatic hypoglycemia has occurred in children and infants who received mercaptopurine for the treatment of acute lymphoblastic leukemia. Cases of hypoglycemia occurred in pediatric patients less than 6 years of age or who had a low body mass index.

    Intrauterine fetal death, pregnancy

    Mercaptopurine may cause fetal harm when administered during pregnancy; intrauterine fetal death has been reported. Females of reproductive potential should avoid becoming pregnant while receiving mercaptopurine. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. Women receiving mercaptopurine in the first trimester have an increased incidence of fetal loss; the risk of malformation in offspring surviving the first trimester is not known. In a report of 28 women who received mercaptopurine after the first trimester, 3 patients died undelivered, 1 patient experienced intrauterine fetal death, and 1 patient aborted; there were no cases of macroscopically abnormal fetuses.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during mercaptopurine treatment. Pregnancy testing is recommended for females of reproductive potential prior to starting mercaptopurine. These patients should use effective contraception during and for 6 months after the last mercaptopurine dose. Patients who become pregnant while receiving mercaptopurine should be apprised of the potential hazard to the fetus. Due to male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during therapy and for 3 months after the last mercaptopurine dose. Based on finding from animal studies, infertility/impaired fertility may occur in males or females who receive mercaptopurine.

    Breast-feeding

    It is not known if mercaptopurine or its metabolites are secreted in human milk or if it has effects on the breastfed child or on milk production. Due to the risk of serious adverse reactions in the breastfed child, women should discontinue breast-feeding during mercaptopurine therapy and for 1 week after the last dose.

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / 0-3.3
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    spontaneous fetal abortion / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    skin cancer / Delayed / Incidence not known
    lymphoma / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known

    Moderate

    jaundice / Delayed / 0-40.0
    oral ulceration / Delayed / 0-5.0
    hyperuricemia / Delayed / 0-5.0
    elevated hepatic enzymes / Delayed / 0-5.0
    hyperbilirubinemia / Delayed / 0-5.0
    thrombocytopenia / Delayed / 20.0
    neutropenia / Delayed / 20.0
    anemia / Delayed / 20.0
    lymphopenia / Delayed / 20.0
    bleeding / Early / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    ascites / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known

    Mild

    nausea / Early / 5.0-20.0
    anorexia / Delayed / 5.0-20.0
    vomiting / Early / 5.0-20.0
    diarrhea / Early / 5.0-20.0
    rash / Early / 5.0-20.0
    malaise / Early / 5.0-20.0
    infection / Delayed / 0-5.0
    skin hyperpigmentation / Delayed / 0-5.0
    urticaria / Rapid / 0-5.0
    fever / Early / 0-1.0
    alopecia / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known

    DRUG INTERACTIONS

    Allopurinol: (Major) The concomitant use of mercaptopurine and allopurinol may result in increased mercaptopurine toxicity (e.g., bone marrow suppression, nausea, and vomiting). If these drugs are used together, reduce the mercaptopurine dose to one-third to one-quarter of the usual dose to avoid severe toxicity. Allopurinol inhibits xanathine oxidase; mercaptopurine is inactivated via the xanathine oxidase enzyme.
    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Azathioprine: (Contraindicated) Mercaptopurine, 6-MP is an active metabolite of azathioprine. Concurrent usage is, in essence, a duplication of pharmacologic therapy and may lead to overdosage. Co-therapy of azathioprine and 6-MP should be avoided to reduce the risk of a serious potential for drug-induced side effects and toxicity; case reports of severe immunosuppression and bone marrow suppression have occurred, and some of these cases have resulted in hospitalization, sepsis, and even patient mortality.
    Azelastine; Fluticasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Balsalazide: (Moderate) Increased myelosuppression may occur if mercaptopurine is coadministered with balsalazide. If concomitant use is necessary, use the lowest possible doses of each drug and closely monitor the patient for bone marrow suppression. 5-Aminosalicylates, such as balsalazide, have been shown to inhibit the thiopurine methyltransferase (TPMT) enzyme in vitro. Mercaptopurine is inactivated via the TPMT enzyme.
    Basiliximab: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents may result in additive effects. A dosage reduction of the purine analog may be indicated when used in combination with other myelosuppressive chemotherapy.
    Beclomethasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Betamethasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Budesonide: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Budesonide; Formoterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Budesonide; Glycopyrrolate; Formoterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Ciclesonide: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Corticosteroids: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Cortisone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Cyclosporine: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
    Deflazacort: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Dexamethasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Doxorubicin Liposomal: (Moderate) Use mercaptopurine and doxorubicin together with caution; doxorubicin may potentiate mercaptopurine-induced hepatotoxicity. If these drugs are used together, monitor patients for signs and symptoms of hepatic dysfunction. Additionally, a mercaptopurine dosage reduction may be required when it is used in combination with other myelosuppressive agents such as doxorubicin. Hepatic dysfunction (i.e., hyperbilirubinemia, elevated AST and alkaline phosphatase levels) occurred in all 11 patients with refractory leukemia who received mercaptopurine (500 mg/m2 IV daily for 5 days) and doxorubicin (50 mg/m2 IV) repeated every 2 to 3 weeks; some patients also received vincristine and prednisone. Hepatotoxicity was observed in 19 of 20 patients who received mercaptopurine and doxorubicin as induction therapy for resistant leukemia in another report.
    Doxorubicin: (Moderate) Use mercaptopurine and doxorubicin together with caution; doxorubicin may potentiate mercaptopurine-induced hepatotoxicity. If these drugs are used together, monitor patients for signs and symptoms of hepatic dysfunction. Additionally, a mercaptopurine dosage reduction may be required when it is used in combination with other myelosuppressive agents such as doxorubicin. Hepatic dysfunction (i.e., hyperbilirubinemia, elevated AST and alkaline phosphatase levels) occurred in all 11 patients with refractory leukemia who received mercaptopurine (500 mg/m2 IV daily for 5 days) and doxorubicin (50 mg/m2 IV) repeated every 2 to 3 weeks; some patients also received vincristine and prednisone. Hepatotoxicity was observed in 19 of 20 patients who received mercaptopurine and doxorubicin as induction therapy for resistant leukemia in another report.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Febuxostat: (Contraindicated) The use of febuxostat with mercaptopurine is contraindicated. Febuxostat inhibits xanthine oxidase (XO) and is expected to greatly increase the concentrations of drugs metabolized substantially by this enzyme, such as mercaptopurine. Inhibition of XO by febuxostat may cause increased plasma concentrations of mercaptopurine, 6-MP, leading to serious toxicity. Drug interaction studies of febuxostat with mercaptopurine have not been conducted.
    Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Fludrocortisone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Flunisolide: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Fluticasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Fluticasone; Salmeterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Fluticasone; Vilanterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Formoterol; Mometasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Hydrocortisone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Infliximab: (Moderate) Post-marketing fatal cases of hepatosplenic T-cell lymphoma have been reported, mostly in adolescent and young adult males with inflammatory bowel disease such as Crohn's disease or ulcerative colitis; almost all cases have occurred in patients who had received a TNF blocker such as infliximab concomitantly with either mercaptopurine, 6-MP or azathioprine at or before diagnosis. It is unknown whether the occurrence of hepatosplenic T-cell lymphoma is related to a TNF blocker or to a TNF blocker in combination with these other immunosuppressants. Use with caution.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Lesinurad; Allopurinol: (Major) The concomitant use of mercaptopurine and allopurinol may result in increased mercaptopurine toxicity (e.g., bone marrow suppression, nausea, and vomiting). If these drugs are used together, reduce the mercaptopurine dose to one-third to one-quarter of the usual dose to avoid severe toxicity. Allopurinol inhibits xanathine oxidase; mercaptopurine is inactivated via the xanathine oxidase enzyme.
    Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Mesalamine, 5-ASA: (Moderate) Increased bone marrow suppression may occur if mercaptopurine is coadministered with mesalamine. If concomitant use is necessary, use the lowest possible doses of each drug and closely monitor the patient for myelosuppression. 5-Aminosalicylates, such as mesalamine, have been shown to inhibit the thiopurine methyltransferase (TPMT) enzyme in vitro. Mercaptopurine is inactivated via the TPMT enzyme.
    Methylprednisolone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Mometasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Natalizumab: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. Natalizumab for Crohn's disease should not be used in combination with immunosuppressants such as 6-mercaptopurine. Ordinarily, patients with mulitple sclerosis who are receiving chronic immunosuppressant therapy should not be treated with natalizumab, for similar reasons.
    Olsalazine: (Moderate) Increased bone marrow suppression may occur if mercaptopurine is coadministered with olsalazine. If concomitant use is necessary, use the lowest possible doses of each drug and closely monitor the patient for myelosuppression. 5-Aminosalicylates, such as olsalazine, have been shown to inhibit the thiopurine methyltransferase (TPMT) enzyme in vitro. Mercaptopurine is inactivated via the TPMT enzyme.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
    Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with mercaptopurine. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
    Platelet Inhibitors: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Porfimer: (Major) Avoid coadministration of porfimer with mercaptopurine due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like mercaptopurine may increase the risk of a photosensitivity reaction.
    Prednisolone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Prednisone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and mercaptopurine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Ropeginterferon alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Increased bone marrow suppression may occur if mercaptopurine is coadministered with trimethoprim sulfamethoxazole. If concomitant use is necessary, monitor complete blood counts and adjust the dose of mercaptopurine if severe neutropenia or thrombocytopenia occur.
    Sulfasalazine: (Moderate) Increased bone marrow suppression may occur if mercaptopurine is coadministered with sulfasalazine. If concomitant use is necessary, use the lowest possible doses of each drug and closely monitor the patient for myelosuppression. 5-Aminosalicylates, such as sulfasalazine, have been shown to inhibit the thiopurine methyltransferase (TPMT) enzyme in vitro. Mercaptopurine is inactivated via the TPMT enzyme.
    Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Tofacitinib: (Major) Concomitant use of tofacitinib in combination with potent immunosuppressants such as mercaptopurine is not recommended. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Triamcinolone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Upadacitinib: (Major) The use of upadacitinib in combination with potent immunosuppressants such as mercaptopurine is not recommended. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with mercaptopurine is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like mercaptopurine may increase the risk of a photosensitivity reaction.
    Warfarin: (Major) The concomitant use of mercaptopurine and warfarin may decrease the anticoagulant effectiveness of warfarin. If concurrent use is required, monitor prothrombin time or INR and adjust the warfarin dose to maintain the desired level of anticoagulation.
    Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Mercaptopurine may cause fetal harm when administered during pregnancy; intrauterine fetal death has been reported. Females of reproductive potential should avoid becoming pregnant while receiving mercaptopurine. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. Women receiving mercaptopurine in the first trimester have an increased incidence of fetal loss; the risk of malformation in offspring surviving the first trimester is not known. In a report of 28 women who received mercaptopurine after the first trimester, 3 patients died undelivered, 1 patient experienced intrauterine fetal death, and 1 patient aborted; there were no cases of macroscopically abnormal fetuses.

    MECHANISM OF ACTION

    Mercaptopurine (6-MP) is activated via hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) to form 6-thioguanine nucleotides (6-TGN) and thioinosinic acid (TIMP). Additionally, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. 6-TGN is incorporated into nucleic acids in place of purine bases resulting in cell-cycle arrest and cell death. TIMP nucleotide inhibits several reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid via adenylosuccinate. TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of IMP dehydrogenase and XMP aminase, converting TIMP to thioguanylic acid.

    PHARMACOKINETICS

    Mercaptopurine is administered orally. It has a Vd exceeding that of total body water (0.9 L/kg) and has minimal cerebrospinal fluid penetration. The plasma protein binding averaged 19% following an investigational IV formulation of mercaptopurine at doses exceeding 5 to 10 mg/kg. The median elimination half-life of mercaptopurine oral suspension is 1.3 hours (range, 0.9 to 5.4 hours). The elimination half-life of mercaptopurine oral suspension is approximately 2 hours. Mercaptopurine is metabolized via 2 major pathways: thiol methylation and oxidation. Thiol methylation is catalyzed by the polymorphic enzyme thiopurine S-methyltransferase (TPMT) to an inactive metabolite, methyl-mercaptopurine. TPMT activity is highly variable in patients due to a genetic polymorphism in the TPMT gene. During oxidation, mercaptopurine is catalyzed via xanthine oxidase to another inactive metabolite, 6-thiouric acid. Following the oral administration of radiolabeled mercaptopurine in 1 subject, 46% of the dose was excreted in the urine as parent drug and metabolites within the first 24 hours.

    Oral Route

    Oral mercaptopurine has demonstrated incomplete and variable absorption in clinical studies; approximately 50% of the dose is absorbed. Following a single oral dose of mercaptopurine 50 mg in healthy adults under fasted conditions, the mean AUC(0 to inf) value was 129 ng X hour/mL and the mean Cmax was 69 ng/mL. The median Cmax and AUC(0 to inf) values were 93 ng/mL (range, 40 to 204 ng/mL) and 136 ng X hour/mL (range, 77 to 268 ng X hour/mL), respectively, following a single 50 mg dose of mercaptopurine oral suspension in adults under fasting conditions. The Tmax was 0.75 hours (range, 0.33 to 2.5 hours).
    Effects of food: Administering mercaptopurine with food results in decreased drug exposure.