Brand names: Purinethol, Purixan
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Nov 17, 2023. Written by ASHP.

Introduction

Antineoplastic and immunosuppressive agent; purine antagonist.¹⁰³

Uses for Mercaptopurine

Acute Lymphoblastic Leukemia (ALL)

Treatment of adults and pediatric patients with ALL as maintenance therapy in combination with other drugs.^{103 105 138}

Crohn Disease

Has been used for management of moderate to severe or chronically active Crohn disease^{† [off-label]}.^{100 101 102 106 107 108 110 111 112 113 114 115 116 118 121 125 126 139}

The American Gastroenterological Association (AGA) and American College of Gastroenterology (ACG) guidelines state that thiopurines are generally used for maintenance of remission or in combination with other therapies (e.g., tumor necrosis factor [TNF] blocking agents) for induction and maintenance of remission in patients with moderate to severe Crohn disease.^{139 140}

Ulcerative Colitis

Has been used in the management of ulcerative colitis^{† [off-label]}.¹⁰²

AGA guideline suggests the use of thiopurine monotherapy for maintenance of remission in patients with moderate to severe ulcerative colitis; thiopurines also may be used in combination with TNF blocking agents, vedolizumab, or ustekinumab for remission induction.¹⁴¹

Mercaptopurine Dosage and Administration

General

Pretreatment Screening

• Consider genetic testing (i.e., TPMT and NUDT15) or use of previous testing results to guide dosing recommendations.¹³⁶

• Verify pregnancy status in females of reproductive potential.¹⁰³

Patient Monitoring

• Monitor CBC and adjust dose to maintain ANC at desired level and avoid excessive myelosuppression.¹⁰³

• Monitor serum transaminase, alkaline phosphatase, and bilirubin at weekly intervals when first beginning therapy and at monthly intervals thereafter.¹⁰³ Monitor liver tests more frequently in patients receiving other hepatotoxic drugs or those with pre-existing liver disease.¹⁰³

• Monitor for lymphoproliferative disorders and other malignancies such as skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non- Kaposi's), and uterine cervical cancer in situ.¹⁰³

• Monitor for the development of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection.^{100 103}

Dispensing and Administration Precautions

• Handling and Disposal: Mercaptopurine is a cytotoxic drug; consult specialized references for procedures for proper handling and disposal.¹⁰³

• Based on the Institute for Safe Medication Practices (ISMP), mercaptopurine is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.¹⁴²

Administration

Oral Administration

Administer orally as tablets or oral suspension.^{103 137} Take consistently, either with or without food.^{103 137}

Do not administer tablets to patients who are unable to swallow tablets; use the oral suspension in these patients. ¹³⁷

Shake the oral suspension for at least 30 seconds to mix.¹³⁷ Use oral dispensing syringes to measure and dispense the dose.¹³⁷ Use the suspension within 8 weeks; properly discard any remaining suspension after that time.¹³⁷

If a dose is missed, skip the dose and continue therapy with the next dose.¹⁰³

Pharmacogenomic Testing

Pharmacogenomic testing for thiopurine S-methyltransferase (TPMT) and nucleotide diphosphatase (NUDT15) may be useful for identifying patients at increased risk for life-threatening myelosuppression, or evaluating those with severe myelosuppression or repeated episodes of myelosuppression during treatment.^{103 136} Patients with specific variants of TPMT and NUDT15 are likely to have increased systemic exposure to mercaptopurine and are at increased risk of myelosuppression.^{103 136}

Dosage

Pediatric Patients

Acute Lymphoblastic Leukemia (ALL)

Maintenance Therapy

Oral

Usually, 1.5–2.5 mg/kg once daily as part of a combination chemotherapy regimen.^{103 137}

Adults

ALL

Maintenance Therapy

Oral

Usually 1.5–2.5 mg/kg once daily as part of a combination chemotherapy regimen.¹⁰³

Crohn Disease† [off-label]

Oral

Maximal dosage of 0.75–1.5 mg/kg daily.¹⁴⁰

Dosage Modifications in Patients with TPMT and NUDT15 Deficiency

TPMT intermediate or TPMT possible intermediate metabolizer: Start with reduced doses of mercaptopurine (30-80% of normal dose) if starting dose is ≥75 mg/m²/day or ≥1.5 mg/kg/day (e.g., start at 22.5-60 mg/m²/day or 0.45-1.2 mg/kg/day) and adjust doses based on degree of myelosuppression and disease specific guidelines.¹³⁶ Allow 2–4 weeks to reach steady state after each dosage adjustment.¹³⁶ If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents, dependent on concomitant therapy.¹³⁶ If normal starting dose is <75 mg/m²/day or <1.5 mg/kg/day, dose reduction may not be recommended.¹³⁶

TPMT poor metabolizer: For malignancy, start with drastically reduced doses of mercaptopurine (reduce daily dose by 10-fold and reduce frequency to three times weekly instead of daily (e.g., 10 mg/m²/day given just 3 days/week) and adjust doses based on degree of myelosuppression and disease specific guidelines.¹³⁶ Allow 4–6 weeks to reach steady state after each dosage adjustment.¹³⁶ If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.¹³⁶ For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy.¹³⁶

NUDT15 intermediate or NUDT15 possible intermediate metabolizer: Start with reduced mercaptopurine doses (30−80% of normal dose) if normal starting dose is ≥75 mg/m²/day or ≥1.5 mg/kg/day (e.g., start at 22.5–60 mg/m²/day or 0.45–1.2 mg/kg/day) and adjust doses based on degree of myelosuppression and disease-specific guidelines.¹³⁶ Allow 2–4 weeks to reach steady state after each dosage adjustment.¹³⁶ If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents, depending on other therapy.¹³⁶ If normal starting dose is <75 mg/m²/day or <1.5 mg/kg/day, dose reduction may not be recommended.¹³⁶

NUDT15 poor metabolizer: For malignancy, initiate mercaptopurine at 10 mg/m²/day and adjust dose based on myelosuppression and disease-specific guidelines.¹³⁶ Allow 4–6 weeks to reach steady state after each dosage adjustment.¹³⁶ If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.¹³⁶ For non-malignant conditions, consider alternative nonthiopurine immunosuppressant therapy.¹³⁶

Special Populations

Hepatic Impairment

Use lowest recommended starting dosage.¹⁰³ Adjust dosage to maintain ANC at a desirable level and for management of adverse reactions.¹⁰³

Renal Impairment

Use lowest recommended starting dosage in patients with renal impairment (Cl_cr <50 mL/minute).¹⁰³ Adjust dosage to maintain ANC at a desirable level and for management of adverse reactions.¹⁰³

Geriatric Use

Select dosage with caution, usually starting at the low end of the dosing range.¹⁰³

Cautions for Mercaptopurine

Contraindications

• None.¹⁰³

Warnings/Precautions

Warnings

Myelosuppression

Most consistent, dose-related adverse reaction is myelosuppression, manifested by anemia, leukopenia, thrombocytopenia, or any combination of these effects.¹⁰³

Individuals who are homozygous deficient (2 nonfunctional alleles; poor metabolizer) for an inherited defect in theTPMT gene are unusually sensitive to myelosuppressive effects of mercaptopurine and prone to rapid bone marrow suppression.¹⁰³ Substantial dosage reductions generally are required in such patients to avoid life-threatening suppression.¹⁰³ Tolerance may vary in individuals who are heterozygous deficient (one nonfunctional allele; intermediate metabolizer) for the defect in theTPMT gene.^{103 137} Although some of these patients may experience greater toxicity, most will tolerate usual doses.¹⁰³

Monitor CBC and adjust dosage for excessive myelosuppression.¹⁰³ Consider testing for TPMT or NUDT15 deficiency in patients with severe myelosuppression or repeated episodes of myelosuppression.¹⁰³ Patients with heterozygous or homozygous TPMT or NUDT15 deficiency may require dose reduction.¹⁰³

Concomitant use of allopurinol may exacerbate myelotoxicity.¹⁰³ Reduction of mercaptopurine dosage is required.¹⁰³

Hepatotoxicity

Mercaptopurine is hepatotoxic; may be associated in some cases with anorexia, diarrhea, jaundice, and ascites.¹⁰³ Hepatic encephalopathy and deaths attributed to hepatic necrosis reported.¹⁰³

Hepatic injury occurs with any dosage, but may occur with greater frequency when recommended dosage exceeded.¹⁰³

Clinically detectable jaundice usually appears early in treatment (1 to 2 months); however, it has been reported at 1 week and as late as 8 years after starting mercaptopurine.¹⁰³ In some patients, jaundice resolved following withdrawal, but reappeared with rechallenge.¹⁰³

Monitor serum transaminase levels, alkaline phosphatase, and bilirubin levels at weekly intervals when beginning therapy and at monthly intervals thereafter.¹⁰³ Monitor liver tests more frequently in patients receiving mercaptopurine with other hepatotoxic drugs or those with pre-existing liver disease.¹⁰³ Withhold mercaptopurine at onset of hepatotoxicity.¹⁰³

Immunosuppression

May impair immune response to infectious agents or vaccines.¹⁰³ Due to immunosuppression associated with maintenance chemotherapy for ALL, response to all vaccines may be diminished and there is a risk of infection with live virus vaccines.¹⁰³

Consult immunization guidelines for recommendations regarding immunocompromised patients.¹⁰³

Treatment-related Malignancies

May increase risk of neoplasia.¹⁰³ Monitor for occurrence of malignancies.¹³⁵

Hepatosplenic T-cell lymphoma, a rare, aggressive, usually fatal malignancy, reported in mercaptopurine-treated patients with inflammatory bowel disease (IBD)^{† [off-label]}.^{103 135}

Patients receiving immunosuppressive therapy, including mercaptopurine, are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non- Kaposi's) and uterine cervical cancer in situ.¹⁰³

Risk appears to be related to degree and duration of immunosuppression.¹⁰³ Discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.¹⁰³ Treatment regimens containing multiple immunosuppressants (including thiopurines) should be used with caution as this could lead to potentially fatal lymphoproliferative disorders.¹⁰³ A combination of concomitantly administered multiple immunosuppressants increases risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.¹⁰³

Macrophage Activation Syndrome

Macrophage activation syndrome (MAS; hemophagocytic lymphohistiocytosis) may develop in patients with autoimmune conditions, in particular those with IBD^{† [off-label]} .¹⁰³ Patients receiving mercaptopurine may have increased susceptibility for this condition.¹⁰³

Discontinue mercaptopurine if MAS occurs or is suspected.¹⁰³

Monitor for and promptly treat infections such as EBV and CMV, as these are known triggers for MAS.¹⁰³

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.¹⁰³ Women who receive mercaptopurine during the first trimester have increased incidence of miscarriage.¹⁰³ Miscarriage and stillbirth reported in women who receive mercaptopurine after first trimester of pregnancy.¹⁰³

Specific Populations

Pregnancy

Can cause fetal harm.¹⁰³ Increased incidence of miscarriage and stillbirth.¹⁰³ Advise pregnant women of the potential risk to a fetus.¹⁰³

Lactation

No data on presence of mercaptopurine or its metabolites in human milk, effects on the breastfed child, or effects on milk production.¹⁰³

Advise women not to breastfeed during treatment with mercaptopurine and for 1 week after final dose¹⁰³

Females and Males of Reproductive Potential

Can cause fetal harm when administered to pregnant women.¹⁰³

Verify pregnancy status in females of reproductive potential prior to initiating mercaptopurine.¹⁰³

Advise females of reproductive potential to use effective contraception during treatment and for 6 months after final dose.¹⁰³ Advise males with female partners of reproductive potential to use effective contraception during treatment with mercaptopurine and for 3 months after final dose.¹⁰³

Based on findings from animal studies, can impair female and male fertility.¹⁰³ Long-term effects, including reversibility, not studied.¹⁰³

Pediatric Use

Safety and effectiveness not established, but use is supported by evidence from published literature and clinical experience.¹⁰³

Symptomatic hypoglycemia reported in pediatric patients with ALL.¹⁰³ Reported cases were in children <6 yearsof age or those with a low BMI.¹⁰³

Geriatric Use

Insufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients.¹⁰³ Other clinical experience has not identified differences in responses between elderly and younger patients.¹⁰³

Common Adverse Effects

ALL

Common adverse effects (>20%): myelosuppression, including anemia, neutropenia, lymphopenia, thrombocytopenia.¹⁰³

Common adverse effects (5–20%): anorexia, nausea, vomiting, diarrhea, malaise, rash.¹⁰³

Drug Interactions

Myelosuppressive Drugs

Possible increased risk of myelosuppression; consider reducing mercaptopurine dosage if used concomitantly.¹⁰³ Monitor CBC and adjust dose for excessive myelosuppression.¹⁰³

Hepatotoxic Drugs

Possible increased risk of hepatotoxicity; use concomitantly with caution and monitor hepatic function closely.¹⁰³

Specific Drugs

Mercaptopurine Pharmacokinetics

Absorption

Bioavailability

Food may decrease exposure of mercaptopurine.¹⁰³

Distribution

Extent

Only negligible concentrations attained in CSF.¹⁰³

Not known whether mercaptopurine is distributed into human milk.¹⁰³

Plasma Protein Binding

Approximately 19%.¹⁰³

Elimination

Metabolism

Rapidly and extensively metabolized in liver by oxidation via xanthine oxidase to 6-thiouric acid.¹⁰³ Also undergoes thiol methylation via the enzyme TPMT to form inactive metabolite, methyl-6-MP.¹⁰³

Elimination Route

Excreted principally in urine (about 46%) as unchanged drug and metabolites within first 24 hours.¹⁰³

Half-life

<2 hours after single oral dose.¹⁰³

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted to 15-30ºC).¹⁰³

Suspension

15–25°C.¹³⁷

Actions

• Nucleoside metabolic inhibitor.¹⁰³

• Converted intracellularly to ribonucleotides that result in a sequential blockade of the synthesis and utilization of purine nucleotides.¹⁰³

• Inhibits synthesis of RNA and DNA.¹⁰³

• Also an immunosuppressant that inhibits primary immune response.^{103 134 136}

Advice to Patients

• Advise patients and caregivers that mercaptopurine can cause myelosuppression, hepatotoxicity, and GI toxicity.¹⁰³ Advise patients to contact their healthcare provider if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia.¹⁰³

• Instruct patients to minimize sun exposure due to risk of photosensitivity.¹⁰³

• Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.¹⁰³ Advise females of reproductive potential to use effective contraception during treatment with mercaptopurine and for 6 months after the final dose.¹⁰³ Advise males with female partners of reproductive potential to use effective contraception during treatment with mercaptopurine and for 3 months after the final dose.¹⁰³

• Advise males and females of reproductive potential that mercaptopurine can impair fertility.¹⁰³

• Advise women not to breastfeed during treatment with mercaptopurine and for 1 week after the final dose.¹⁰³

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., allopurinol) or OTC drugs, as well as concomitant illnesses.¹⁰³

• Inform patients of other important precautionary information¹⁰³

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Medical Disclaimer