AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Mercaptopurine

Mercaptopurine, a purine antagonist, is an antineoplastic agent and immunosuppressant.104

Acute Lymphoblastic Leukemia

Mercaptopurine is used in adults and pediatric patients for the treatment of acute lymphoblastic leukemia (ALL) as maintenance therapy in combination with other drugs.103,105

For management of childhood ALL, most protocols include remission induction chemotherapy at the time of diagnosis followed by postinduction therapy after achieving complete remission; postinduction therapy consists of consolidation/intensification and maintenance therapy.105 Mercaptopurine may be used in combination with other drugs (i.e., cyclophosphamide, low-dose cytarabine, intrathecal therapy) as part of initial consolidation† immediately following the initial induction phase.105 Daily mercaptopurine is also typically used as maintenance therapy in combination with weekly low-dose methotrexate and sometimes intermittent treatment with vincristine and a corticosteroid, along with continued intrathecal therapy.105 Mercaptopurine is the standard drug of choice in the thiopurine class because of increased toxicity of other agents.105

For managment of adults with ALL, most protocols include remission induction therapy, CNS prophylaxis, and postremission (remission continuation or maintenance) therapy.138 Mercaptopurine may be used in combination with methotrexate as maintenance treatment.103 Because the optimal postremission therapy for patients with ALL is not known, patients are encouraged to participate in clinical trials.138

Crohn Disease

Mercaptopurine has been used in the management of moderate to severe or chronically active Crohn disease†; the drug has been shown to induce clinical remission in corticosteroid-dependent patients and to provide benefit in patients with fistulizing Crohn disease.100,101,102,106,107,108,110,111,112,113,114,115,116,118,120,121,125,126 139

The American Gastroenterological Association (AGA) and the American College of Gastroenterology (ACG) have issued guidelines for the treatment of Crohn Disease.139 140 Immunodulators such as thiopurines are one of several drug classes used in Crohn disease management.139 140 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 The ACG guideline specifically states that thiopurines (azathioprine, 6-mercaptopurine) are effective and should be considered for steroid-sparing and maintenance treatment in moderate to severe Crohn disease.140

Ulcerative Colitis

Mercaptopurine has been used in the treatment of ulcerative colitis†.102,141

Immunodulators, such as thiopurines, are one of several drug classes used in the treatment of ulcerative colitis.141 The AGA guideline for the management of moderate to severe ulcerative colitis suggests the use of thiopurine monotherapy for maintenance of remission.141 AGA also suggests against the use of thiopurine monotherapy for induction of remission; however, thiopurines may be used in combination with TNF blocking agents, vedolizumab, or ustekinumab for remission induction.141

General

Pretreatment Screening

• Consider genetic testing (i.e., thiopurine S-methyltransferase [TPMT] and nucleotide diphosphatase [NUDT15] ) or use of previous testing results to guide dosing recommendations.136
• Verify pregnancy status in females of reproductive potential. 103

Patient Monitoring

• Monitor complete blood count (CBC) and adjust dosage to maintain the absolute neutrophil count (ANC) at desired level and to avoid excessive myelosuppression.103
• Monitor serum transaminase levels, alkaline phosphatase, and bilirubin levels 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.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

Mercaptopurine is administered orally as tablets or an oral suspension.103,137 Take consistently, either with or without food.103

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

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

If a dose of mercaptopurine is missed, skip the dose and continue therapy with the next dose.103,137

Pharmacogenomic Testing

Pharmacogenomic testing for thiopurine S-methyltransferase (TPMT ) and nucleotide diphosphatase ( NUDT15 ) genotypes 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 Commercially available tests are used to identify patients who are either homozygous or heterozygous for the nonfunctional allele of the TPMT or NUDT15 gene.103,130,131,134,136 Patients with a specific genetic variant of TPMT or NUDT15 , or a combination of both, may be more likely to have increased systemic exposure to mercaptopurine and risk of myelosuppression and; therefore, may require a dose reduction.103,136

Among patients of European or African ancestory, about 10% of patients will have one nonfunctional allele of the TPMT gene (heterozygous deficient) causing low or intermediate TPMT activity.103 In these patients, higher concentrations of thioguanine nucleotides will accumulate, making mercaptopurine toxicity more likely.103,131 About 0.3% (approximately 1 in 300 patients) will have 2 nonfunctional alleles of the TPMT gene (homozygous deficient) causing little or no detectable TPMT activity.103

NUDT15 deficiency is detected in <1% of patients of European or African ancestry.103 Among patients of East Asian ancestry (i.e., Chinese, Japanese, Vietnamese), 2% have 2 loss-of-function alleles of the NUDT15 gene causing low NUDT15 activity, and approximately 21% have 1 loss of-function allele causing intermediate NUDT15 activity.136 Inherited NUDT15 deficiency is also common in Hispanic populations, particulary those with high levels of Native American genetic ancestry.136 Genotyping in these populations may be useful to guide clinical decisions and dosing.136

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has provided dosing guidelines for mercaptopurine based on results of TPMT and NUDT15 genotyping.136 CPIC recommends that the dosage of mercaptopurine be reduced intially based on results of TPMT or NUDT15 genotypes associated with an intermediate metabolizer phenotype (or possible intermediate metabolizer if uncertain/unknown function alleles).136 For TPMT or NUDT15 genotypes associated with poor metabolizer status, CPIC recommends drastically reduced mercaptopurine dosages for treatment of malignancy and, for nonmalignant conditions, consideration of another therapy.136 For patients with intermediate metabolizer status for both TPMT and NUDT15 , further reduction in dosage may be necessary based on the possibility of lower thiopurine tolerance.136 If test results are known for only one gene (either TPMT or NUDT15 ), prescribing recommendations may be implemented initially, with the knowledge that the missing information may have important implications.136 The limitations of TPMT or NUDT15 genotyping should be considered when interpreting and applying the results of these tests.136 For additional information and guidance on how to interpret and apply the results of TPMT and NUDT15 testing, the CPIC guideline for thiopurine dosing based on HLA genotypes should be consulted.136

Dosage

Acute Lymphoblastic Leukemia (ALL)

For maintenance therapy of ALL in adults and pediatric patients, the recommended starting dosage of mercaptopurine is 1.5-2.5 mg/kg orally once daily as part of a combination chemotherapy regimen.103,137 Adjust dosage based on ANC.103,137 For the tablet formulation, a recommended dosage for patients <17 kg is not achievable, as the only available strength is 50 mg.103

Dosage Modifications in Patients with TPMT and NUDT15 Deficiency

TPMT intermediate or TPMT possible intermediate metabolizer: CPIC guidelines recommend to 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 the dosage of mercaptopurine over other agents, depending on other therapy.136 If the normal starting dose is already <75 mg/m²/day or <1.5 mg/kg/day, dosage reduction may not be recommended.136

TPMT poor metabolizer: For malignancy, CPIC guidelines state to 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, an emphasis should be on reducing the dosage of 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 the normal starting dose is already <75 mg/m²/day or <1.5 mg/kg/day, dosage reduction may not be recommended.136

NUDT15 poor metabolizer: For malignancy, CPIC guidelines state to initiate the mercaptopurine dose 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 the dosage of mercaptopurine over other agents.136 For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy.136

Inflammatory Bowel Disease

For the management of Crohn disease†, adults may receive mercaptopurine at a maximal dosage of 0.75-1.5 mg/kg daily.140

Special Populations

Hepatic Impairment

Use the lowest recommended starting dosage for mercaptopurine in patients with hepatic impairment.103 Adjust the dosage to maintain ANC at a desirable level and for management of adverse reactions.103

Renal Impairment

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

Geriatric Use

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.103

Contraindications

• None.103

Warnings/Precautions

Myelosuppression

The most consistent dose-related adverse reaction of mercaptopurine is myelosuppression, which is 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 the TPMT gene are unusually sensitive to the myelosuppressive effects of mercaptopurine and are prone to the development of rapid bone marrow suppression following initiation of therapy.103 Substantial dosage reductions generally are required in such patients to avoid the development of life-threatening bone marrow suppression.103 Tolerance of mercaptopurine may vary in individuals who are heterozygous deficient (one nonfunctional allele; intermediate metabolizer) for the defect in the TPMT gene.103 Although some of these patients may experience greater toxicity, most will tolerate usual doses of mercaptopurine.103

Monitor CBC and adjust the dosage of mercaptopurine for excessive myelosuppression.103 Consider testing for TPMT or NUDT15 deficiency in patients with severe myelosuppression or repeated episodes of myelosuppression.103 TPMT genotyping or phenotyping (red blood cell TPMT activity) and NUDT15 genotyping can identify patients who have reduced activity of these enzymes.103 Patients with heterozygous or homozygous TPMT or NUDT15 deficiency may require a dose reduction.103

Concomitant use of allopurinol may exacerbate the myelotoxicity associated with mercaptopurine therapy.103 Reduction of mercaptopurine dosage is therefore required.103

Hepatotoxicity

Mercaptopurine may cause hepatotoxicity.103 Hepatotoxicity has been associated in some cases with anorexia, diarrhea, jaundice, and ascites; hepatic encephalopathy also has occurred.103 There have been reports of deaths attributed to hepatic necrosis associated with the administration of mercaptopurine.103 Hepatic injury can occur with any dosage but seems to occur with greater frequency when the recommended dosage is exceeded.103

Usually, clinically detectable jaundice appears early in the course of treatment (1 to 2 months); however, jaundice has been reported at 1 week and as late as 8 years after starting mercaptopurine.103 In some patients, jaundice has cleared following withdrawal of mercaptopurine and 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

Mercaptopurine is immunosuppressive and may impair the immune response to infectious agents or vaccines.103 Due to the 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

Hepatosplenic T-cell lymphoma has been reported in patients treated with mercaptopurine for inflammatory bowel disease (IBD)†.103

Mercaptopurine is mutagenic in animals and humans, carcinogenic in animals, and may increase the risk of secondary malignancies.103 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

The risk appears to be related to the degree and duration of immunosuppression.103 It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.103 A treatment regimen containing multiple immunosuppressants (including thiopurines) should be used with caution as this may lead to lymphoproliferative disorders, some with reported fatalities.103 A combination of concomitantly administered multiple immunosuppressants increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.103

Macrophage Activation Syndrome

Macrophage activation syndrome (MAS; hemophagocytic lymphohistiocytosis) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular those with IBD†.103 Patients receiving mercaptopurine may have potentially increased susceptibility for developing this condition.103 If MAS occurs or is suspected, discontinue mercaptopurine.103 Monitor for and promptly treat infections such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.103

Embryo-Fetal Toxicity

Mercaptopurine can cause fetal harm when administered to a pregnant woman.103 Women who receive mercaptopurine in the first trimester of pregnancy have an increased incidence of miscarriage.103 Adverse embryo-fetal findings, including miscarriage and stillbirth, have been reported in women who receive mercaptopurine after the first trimester of pregnancy.103

Specific Populations

Pregnancy

Mercaptopurine can cause fetal harm when administered to a pregnant woman.103 Advise pregnant women of the potential risk to a fetus.103

Women receiving mercaptopurine in the first trimester of pregnancy have an increased incidence of miscarria the risk of malformation in offspring surviving first trimester exposure is not known.103 In a series of 28 women receiving mercaptopurine after the first trimester of pregnancy, 3 died prior to delivery, 1 delivered a stillborn child, and 1 aborted; there were no cases of macroscopically abnormal fetuses.103

In animal studies, mercaptopurine was embryo-lethal and teratogenic in several animal species (rat, mouse, rabbit, and hamster) at doses less than the recommended human dose.103

Lactation

There are no data on the presence of mercaptopurine or its metabolites in human milk, the effects on the breastfed child, or effects on milk production.103 Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with mercaptopurine and for 1 week after the final dose.103

Females and Males of Reproductive Potential

Mercaptopurine can cause fetal harm when administered to pregnant women.103 Verify the pregnancy status in females of reproductive potential prior to initiating mercaptopurine.103

Advise females of reproductive potential to use effective contraception during treatment with mercaptopurine and for 6 months after the final dose.103 Based on genotoxicity findings, 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

Based on findings from animal studies, mercaptopurine can impair female and male fertility.103 The long-term effects of mercaptopurine on female and male fertility, including reversibility of effects, have not been studied.103

Pediatric Use

Safety and effectiveness of mercaptopurine have not been established in pediatric patients, but use of the drug in pediatrics is supported by evidence from the published literature and clinical experience.103 105

Symptomatic hypoglycemia has been reported in pediatric patients with ALL receiving mercaptopurine.103 Reported cases were in patients <6 years of age or those with a low body mass index.103

Geriatric Use

Clinical studies of mercaptopurine did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients.103 Other reported clinical experience has not identified differences in responses between the elderly and younger patients.103

Common Adverse Effects

ALL

Common adverse reactions occurring in >20% of patients receiving mercaptopurine include myelosuppression, anemia, neutropenia, lymphopenia, and thrombocytopenia.103

Common adverse reactions occurring in 5-20% of patients receiving mercaptopurine include anorexia, nausea, vomiting, diarrhea, malaise, and rash.103

Myelosuppressive Drugs

Mercaptopurine can cause myelosuppression.103 Myelosuppression may be increased when mercaptopurine is coadministered with other drugs that can cause myelosuppression.103 Monitor CBC and adjust the dose of mercaptopurine for excessive myelosuppression.103

Hepatotoxic Drugs

Mercaptopurine can cause hepatotoxicity.103 Hepatotoxicity may be increased when mercaptopurine is coadministered with other drugs that cause hepatotoxicity.103 Monitor liver function tests more frequently in patients receiving such concomitant therapy.103

Allopurinol

Allopurinol can inhibit the first-pass oxidative metabolism of mercaptopurine by xanthine oxidase, which can lead to an increased risk of mercaptopurine adverse reactions (i.e., myelosuppression, nausea, vomiting).103 Reduce the dose of mercaptopurine by 25-33% when coadministered with allopurinol.103

Warfarin

Concomitant administration of mercaptopurine and warfarin may decrease the anticoagulant effect of warfarin.103 Monitor the international normalized ratio (INR) and adjust the warfarin dosage as appropriate.103

Aminosalicylates

Aminosalicylates (e.g., mesalamine, olsalazine, sulfasalazine) may inhibit the TPMT enzyme, which may increase the risk of myelosuppression when coadministered with mercaptopurine.103 When aminosalicylates and mercaptopurine are used concomitantly, use the lowest possible doses for each drug and monitor more frequently for myelosuppression.103

Trimethoprim-Sulfamethoxazole

Enhanced myelosuppression has been reported in some mercaptopurine-treated patients who were also receiving trimethoprim-sulfamethoxazole.103

Pharmacology

Description

Mercaptopurine, a purine analog, is a nucleoside metabolic inhibitor.103 The drug undergoes intracellular transport and activation to form metabolites including thioguanine nucleotides (TGNs).103 Incorporation of TGNs into DNA or RNA results in cell-cycle arrest and cell death.103 TGNs and other mercaptopurine metabolites are also inhibitors of de novo purine synthesis and purine nucleotide interconversions.103 Mercaptopurine is cytotoxic to proliferating cancer cells in vitro and has antitumor activity in mouse tumor models.103 It is not known which of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death.103

Mercaptopurine is also an immunosuppressant that inhibits the primary immune response.103 134,136

Following a single oral dose of mercaptopurine 50 mg under fasted conditions in healthy individuals, the peak plasma concentration was 69 ng/mL.103 Food has been shown to decrease the exposure of mercaptopurine.103 Plasma protein binding is approximately 19% over the concentration range 10-50 mcg/mL (a concentration achieved only by IV administration of mercaptopurine at doses >5-10 mg/kg).103 There is negligible entry of mercaptopurine into the cerebrospinal fluid.103 Mercaptopurine is inactivated via 2 major pathways.103 One is thiol methylation, which is catalyzed by the polymorphic enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-mercaptopurine.103 The second inactivation pathway is oxidation, which is catalyzed by xanthine oxidase.103 The product of oxidation is the inactive metabolite 6-thiouric acid.103 Mercaptopurine is excreted principally in the urine as unchanged drug and metabolites within the first 24 hours.103 The elimination half-life is less than 2 hours following a single oral dose.103

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 the 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 information.103

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. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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