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Mercaptopurine

Pronunciation

Class: Antineoplastic Agents
VA Class: AN300
CAS Number: 6112-76-1
Brands: Purinethol

Introduction

Antineoplastic and immunosuppressive agent; purine antagonist.a 103

Uses for Mercaptopurine

Acute Lymphocytic Leukemia (ALL)

First-line therapy in combination with methotrexate for maintenance of drug-induced remissions in adult and pediatric patients with ALL.103 104 105 Maintenance therapy is considered essential once a complete hematologic remission is obtained.103

Crohn’s Disease

Management of moderately to severely or chronically active Crohn’s disease.100 101 102 106 107

Maintenance of clinical remission in corticosteroid-dependent patients.100 101 102 106 107 108 110 111 112 113 114 115 116 118 120 121 125 126

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Management of fistulizing Crohn’s disease.100 106 109 115 116 126

Also has been used in pediatric patients with intractable Crohn’s disease, refractory to corticosteroids, sulfasalazine, and/or anti-infectives.122 123 124

Carefully consider risks and benefits of mercaptopurine in patients with inflammatory bowel disease, especially in adolescents and young adults;135 hepatosplenic T-cell lymphoma reported with such use.103 135 (See Malignancies and Lymphoproliferative Disorders under Cautions.)

Ulcerative Colitis

Also has been used for the treatment of ulcerative colitis.102

Carefully consider risks and benefits of mercaptopurine in patients with inflammatory bowel disease, especially in adolescents and young adults;135 hepatosplenic T-cell lymphoma reported with such use.103 135 (See Malignancies and Lymphoproliferative Disorders under Cautions.)

Mercaptopurine Dosage and Administration

General

  • Individualize dosage carefully based on clinical and hematologic response and tolerance of the patient.103 a

Administration

Administer orally.103 a

Administration of mercaptopurine and methotrexate on an evening schedule recommended for maintenance therapy in children with ALL.129

Dosage

Consult published protocols for dosages used in combination regimens and method and sequence of administration.a

Decision to increase or decrease dosage or to continue or discontinue therapy depends on severity and rapidity with which hematologic effects occur.103 (See Hematologic Effects under Cautions.)

Dosage reduction necessary when used concomitantly with allopurinol.103 a (See Specific Drugs under Interactions.)

When initiating mercaptopurine therapy, patients with inherited deficiency of thiopurine S-methyl transferase (TPMT) activity are at increased risk of life-threatening myelotoxicity; substantial dosage reduction may be required.103 (See Hematologic Effects and also see TPMT Testing, under Cautions.)

Pediatric Patients

ALL
Maintenance Therapy
Oral

Usually, 1.5–2.5 mg/kg once daily.103 a

Crohn’s Disease
Oral

1–1.5 mg/kg daily (up to a maximum of 75 mg daily) has been used.123 124

Adults

ALL
Maintenance Therapy
Oral

Usually 1.5–2.5 mg/kg once daily.103 a

Crohn’s Disease
Oral

Initially, 1–1.5 mg/kg daily (up to a maximum of 125 mg daily) has been used.100 106 116 119

Prescribing Limits

Pediatric Patients

Crohn’s Disease
Oral

Maximum 75 mg daily.123 124

Adults

Crohn’s Disease
Oral

Maximum 125 mg daily.106

Special Populations

Hepatic Impairment

Consider dosage reduction.103 a Discontinue therapy if deterioration of liver function tests, jaundice, hepatomegaly, anorexia with tenderness in the right hypochondrion, or other evidence of toxic hepatitis or biliary stasis occurs, until exact etiology determined.103 (See Hepatic Effects under Cautions.)

Renal Impairment

Initiate therapy with lower dosages to avoid increased accumulation of mercaptopurine and its metabolites and increased risk of toxicity.103

Geriatric Patients

Select dosage with caution, usually starting at the low end of the dosing range, because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.103

Patients with TPMT Deficiency

Patients with homozygous TPMT deficiency (i.e., little or no TPMT activity): Substantial dosage reduction required; 103 however, optimal initial dosage not established.103 Some clinicians recommend a reduction to 10% of the usual dosage with further adjustments based on occurrence of myelotoxicity.130 (See Hematologic Effects under Cautions.)

Patients with heterozygous TPMT deficiency (i.e., low or intermediate TPMT activity): Usual dosages generally tolerated, but dosage reduction may be required.103

Cautions for Mercaptopurine

Contraindications

  • Patients whose disease was resistant to prior therapy with the drug.a 103 Consider that there is complete cross-resistance between mercaptopurine and thioguanine.103

  • Known hypersensitivity to mercaptopurine or any ingredient in the formulation.103

Warnings/Precautions

Warnings

Malignancies and Lymphoproliferative Disorders

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.103 135

Hepatosplenic T-cell lymphoma mostly reported in adolescents and young adults with Crohn’s disease or ulcerative colitis receiving a combination of immunosuppressive agents, including tumor necrosis factor (TNF) blocking agents and/or thiopurine analogs (mercaptopurine or azathioprine); however, cases also reported in patients receiving mercaptopurine or azathioprine alone.135 Carefully consider risks and benefits of these agents, especially in adolescents and young adults with Crohn’s disease or ulcerative colitis.135

Patients with certain conditions (e.g., Crohn’s disease) may be at increased risk for lymphoma; may be difficult to measure added risk of TNF blocking agents, azathioprine, and/or mercaptopurine.135

Adequate Patient Evaluation

Highly toxic drug with a low therapeutic index; therapeutic response is not likely to occur without some evidence of toxicity.a Use only under constant supervision by clinicians experienced in therapy with cytotoxic agents.103 Establish diagnosis of ALL prior to initiating therapy.103

Hematologic Effects

Risk of myelosuppression (manifested as anemia, leukopenia, and/or thrombocytopenia);103 a usually dose related and may be delayed.103 Life-threatening infection and bleeding have occurred.103 Myelosuppression also may reflect progression of disease.103

Carefully monitor hematologic status.a 103 Perform CBCs, including platelet count, weekly during therapy.103 Discontinue therapy temporarily at the first sign of an unexpected abnormally large or rapid decrease in leukocytes, platelets, or hemoglobin concentration or abnormal depression of bone marrow not attributable to the disease process or another drug.103 a

Bone marrow examination (aspiration and/or biopsy) may be helpful in distinguishing among progression of leukemia, resistance to therapy, and marrow hypoplasia induced by therapy.103 Bone marrow may appear hypoplastic; however, in some patients it may appear normocellular.103

When initiating mercaptopurine therapy, patients with inherited deficiency of thiopurine S-methyl transferase (TPMT) are unusually sensitive to the myelosuppressive effects of mercaptopurine and are at risk of life-threatening myelotoxicity.103 Tolerance of mercaptopurine may vary in patients who are heterozygous deficient (one nonfunctional allele) for TPMT; toxicity may be increased in these patients, however, most will tolerate usual doses of mercaptopurine.103 (See Special Populations under Dosage and Administration.)

Hepatic Effects

Potentially fatal hepatotoxicity, manifested as jaundice, cholestasis, ascites, hepatic encephalopathy, elevated hepatic enzyme concentrations, hepatic necrosis, and/or severe fibrosis.103 a

Hepatotoxicity usually includes features of both intrahepatic cholestasis and parenchymal cell necrosis;103 may result from direct toxic effect of the drug and/or hypersensitivity reaction.103

Increased risk with dosages >2.5 mg/kg daily; however, hepatic injury can occur at any dosage.103

Carefully monitor hepatic function.103 a Determine serum transaminase, alkaline phosphatase, and bilirubin concentrations at weekly intervals during initiation of therapy and at monthly intervals thereafter.103 a More frequent monitoring recommended in patients with preexisting liver disease or in those receiving other hepatotoxic drugs.a (See Interactions.) Discontinue therapy if deterioration of liver function tests, jaundice, hepatomegaly, anorexia with tenderness in the right hypochondrion, or other evidence of toxic hepatitis or biliary stasis occurs.103

Immunosuppression

Decreased cellular hypersensitivities and impaired allograft rejection.103 a

Induction of immunity to infectious agents or vaccines may be subnormal.103 a

Consider these immunosuppressive effects regarding intercurrent infections and risk of subsequent neoplasia.103 a

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.103 a Increased incidence of abortion during the first trimester of pregnancy.103 a

Avoid use in pregnant women unless benefits outweigh risks.103 a Only use in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.103 127 If used during pregnancy or patient becomes pregnant during therapy, apprise of potential fetal hazard.103

General Precautions

TPMT Testing

Genetically determined differences in TPMT activity may lead to differences in patient response and/or toxicity.103 (See Hematologic Effects under Cautions.) The most common nonfunctional alleles associated with reduced TPMT activity are TPMT*2, TPMT*3A, and TPMT*3C.103 Patients with 2 nonfunctional alleles (homozygous) have deficient TPMT activity; those with 1 nonfunctional allele (heterozygous) have low or intermediate activity.103

Prior to initiation of therapy, determine TPMT genotype or phenotype to identify patients who are either homozygous or heterozygous for the nonfunctional allele of the TPMT gene.103 130 131 134

Consider TPMT testing if patient has clinical or laboratory evidence of severe bone marrow toxicity, especially myelosuppression.103 130 132

Interpret phenotypic test results with caution; concomitant use of some drugs or recent blood transfusions can cause inaccurate measurements of TPMT activity.103

Hyperuricemia

Possible hyperuricemia and/or hyperuricosuria because of extensive purine catabolism accompanying rapid cellular destruction in patients with leukemia.103 Hyperuricemia may be minimized or prevented by adequate hydration, alkalinization of urine, and/or administration of allopurinol.103 (See Specific Drugs under Interactions.)

Pancreatic Effects

Risk of pancreatitis in patients receiving mercaptopurine for treatment of inflammatory bowel disease (i.e., Crohn’s disease, ulcerative colitis).133 If manifestations of pancreatitis (e.g, epigastric pain, back pain, fever, nausea, elevated serum amylase concentration) occur, discontinue therapy permanently.133

Specific Populations

Pregnancy

Category D.103 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether mercaptopurine is distributed into milk.103 Discontinue nursing or the drug.103

Pediatric Use

Hepatosplenic T-cell lymphoma reported in adolescents receiving mercaptopurine for the management of inflammatory bowel disease.135 (See Malignancies and Lymphoproliferative Disorders under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently from younger adults; administer immunosuppressive drugs with caution.103

Hepatic Impairment

Consider dosage reduction.103 Assess hepatic function prior to and frequently during therapy.a (See Special Populations under Dosage and Administration.)

Renal Impairment

Decreased clearance; consider dosage reduction.103 (See Special Populations under Dosage and Administration.)

Common Adverse Effects

Myelosuppression, hepatotoxicity, nausea, vomiting, anorexia.103 a

Interactions for Mercaptopurine

Hepatotoxic Drugs

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

Myelosuppressive Drugs

Possible increased risk of myelosuppression; consider reducing mercaptopurine dosage if used concomitantly.103 a

Specific Drugs

Drug

Interaction

Comments

Allopurinol

Possible decreased mercaptopurine metabolism and increased risk of myelotoxicity103 a (see Hematologic Effects under Cautions)

Reduce mercaptopurine dosage to 25–33% of usual dosage 103 a

Aminosalicylates (mesalamine, olsalazine, sulfasalazine)

Possible decreased mercaptopurine metabolism and increased risk of myelotoxicity103 (see Hematologic Effects under Cautions)

Use concomitantly with caution103

Drugs affecting myelopoiesis (e.g., co-trimoxazole)

Possible increased myelosuppression103

Warfarin

Possible inhibition of anticoagulant effect103

Mercaptopurine Pharmacokinetics

Absorption

Bioavailability

Absorption from GI tract is variable and incomplete; about 50% of an oral dose is absorbed.103 a

Maximum serum concentrations are reached within 2 hours.a

Distribution

Extent

Distributed throughout total body water.a

Only negligible concentrations attained in CSF.a 103

Not known whether mercaptopurine is distributed into milk.a 103

Plasma Protein Binding

Approximately 19% following IV doses >5–10 mg/kg.103

Elimination

Metabolism

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

Elimination Route

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

Half-life

Following IV administration: 21 minutes in pediatric patients and 47 minutes in adults.103 a

Stability

Storage

Oral

Tablets

15–25°C.103 a

Actions

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

  • Inhibits the synthesis of RNA and DNA.a

  • Usually complete cross-resistance between mercaptopurine and thioguanine.103 a

  • Inhibits the primary immune response, selectively suppressing humoral immunity; some inhibition of the cellular immune response also occurs.a

Advice to Patients

  • Potential increased risk of hepatosplenic T-cell lymphoma, especially in adolescents and young adults with inflammatory bowel disease receiving thiopurines (mercaptopurine or azathioprine) and/or TNF blocking agents; importance of advising patients and caregivers of relative risks and benefits of these and other immunosuppressive agents.135 Importance of patients not discontinuing therapy without consulting clinician.135

  • Importance of informing patients and caregivers of the signs and symptoms of malignancies such as hepatosplenic T-cell lymphoma (e.g., splenomegaly hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss), and importance of patients informing clinicians if such signs or symptoms occur.135

  • Importance of informing patients that the major toxicities of the drug are related to myelosuppression, hepatotoxicity, and GI toxicity.103

  • Importance of taking the drug only under medical supervision.103

  • Importance of informing clinicians if fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia occur.103

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; importance of advising women to avoid pregnancy while receiving mercaptopurine.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

  • Importance of informing patients of other important precautionary information.103 (See Cautions.)

Preparations

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

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

Mercaptopurine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

50 mg*

Mercaptopurine Tablets

Purinethol (scored)

Teva

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Mercaptopurine 50MG Tablets (ROXANE): 30/$92.99 or 90/$242.98

Purinethol 50MG Tablets (GATE): 30/$207.99 or 90/$590.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 4, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Present DH, Korelitz BI, Wisch N et al. Treatment of Crohn’s disease with 6-mercaptopurine: a long-term, randomized, double-blind study. N Engl J Med. 1980; 302:981-7. [IDIS 113855] [PubMed 6102739]

101. Sleisenger MH. How should we treat Crohn’s disease? N Engl J Med. 1980; 302:1024-6. Editorial.

102. Sack DM, Peppercorn MA. Drug therapy of inflammatory bowel disease. Pharmacotherapy. 1983; 3:158-76. [IDIS 171371] [PubMed 6136027]

103. Teva Pharmaceuticals. Purinethol (mercaptopurine) tablets prescribing information. Sellersville, PA; 2011 Apr.

104. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52.

105. Childhood acute lymphoblastic leukemia. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 May 30.

106. Korelitz BI, Adler DJ, Mendelsohn RA et al. Long-term experience with 6-mercaptopurine in the treatment of Crohn’s disease. Am J Gastroenterol. 1993; 88:1198-205. [IDIS 318335] [PubMed 8338087]

107. Korelitz BI, Present DH. A history of immunosuppressive drugs in the treatment of inflammatory bowel disease: origins at The Mount Sinai Hospital. Mt Sinai J Med. 2000; 67: 214-26.

108. Bouhnik Y, Lémann M, Mary JY et al. Long-term follow-up of patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine. Lancet. 1996; 347:215-9. [IDIS 359686] [PubMed 8551879]

109. Pearson DC, May GR, Gordon H et al. Azathioprine and 6-mercaptopurine in Crohn’s disease: a meta-analysis. Ann Intern Med. 1995; 123:132-42. [IDIS 349544] [PubMed 7778826]

110. Sandborn WJ. Azathioprine: state of the art in inflammatory bowel disease. Scand J Gastroenterol. 1998; 33(Suppl 225):92-9.

111. Hanauer SB, Sandborn W, and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn’s disease in adults: Practice Guidelines. Am J Gastroenterol. 2001; 96:635-43. [IDIS 461432] [PubMed 11280528]

112. Feagan BG. Maintenance therapy for inflammatory bowel disease. Am J Gastroenterol. 2003; 98(12 Suppl): S6-S17.

113. Podolsky DK. Inflammatory Bowel Disease. N Engl J Med. 2002; 347:417-29. [IDIS 484721] [PubMed 12167685]

114. Scribano M, Prantera C. Review article: medical treatment of moderate to severe Crohn’s disease. Aliment Pharmacol Ther. 2003; 17(Suppl. 2):23-30. [PubMed 12786609]

115. Biancone L, Tosti V, Fina D et al. Review article: maintenance treatment of Crohn’s disease. Aliment Pharmacol Ther. 2003; 17(Suppl. 2):31-37. [PubMed 12786610]

116. American Gastroenterological Association position statement on perianal Crohn’s disease. Gastroenterology. 2003; 125:1503-1507.

118. Hanauer SB, Present DH. The state of the art in the management of inflammatory bowel disease. Rev Gastroenterol Disord. 2003; 3:81-92. [PubMed 12776005]

119. Summers RW, Switz DM, Sessions JT Jr et al. National Cooperative Crohn’s Disease Study: results of drug treatment. Gastroenterology. 1979; 77:847-69. [IDIS 109536] [PubMed 38176]

120. Hanauer SB. Inflammatory bowel disease. N Engl J Med. 1996; 334:841-8. [IDIS 361805] [PubMed 8596552]

121. Markowitz J, Grancher K, Mandel F et al for the Subcommittee on Immunosuppressive Use of the Pediatric IBD Collaborative Research Forum. Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Am J Gastroenterol. 1993; 88:44-8. [IDIS 308848] [PubMed 8420272]

122. Kirschner BS. Differences in the management of inflammatory bowel disease in children and adolescents compared to adults. Neth J Med. 1998; 53:S13-8. [PubMed 9883009]

123. Markowitz J, Rosa J, Grancher K et al. Long-term 6-mercaptopurine treatment in adolescents with Crohn’s disease. Gastroenterology. 1990; 99:1347-51. [IDIS 273729] [PubMed 1976562]

124. Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology. 1998; 115:813-21. [IDIS 415209] [PubMed 9753482]

125. Sandborn W, Sutherland L, Pearson D et al. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. In: The Cochrane Library. Issue 3. Chichester, United Kingdom: update software 2004.

126. Rutgeerts P. Review article: treatment of perianal fistulizing Crohn’s disease. Aliment Pharmacol Ther. 2004; 20(Suppl 4):106-10. [PubMed 15352905]

127. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066] Fed Regist. 1979; 44:37434-67.

128. Department of Health and Human Services, Food and Drug Administration. Subpart B—Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 (4-1-87 Ed.)). 1987:18-24.

129. Schmiegelow K, Glomstein A, Kristinsson J et al. Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO). J Pediatr Hematol Oncol. 1997; 19:102-9. [PubMed 9149738]

130. Andersen JB, Szumlanski C, Weinshilboum RM et al. Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr. 1998; 87:108-11. [PubMed 9510461]

131. Relling MV, Hancock ML, Rivera GK et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. 1999; 91:2001-8. [PubMed 10580024]

132. Evans WE, Hon YY, Bomgaars L et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol. 2001; 19:2293-301. [PubMed 11304783]

133. Haber CJ, Meltzer SJ, Present DH et al. Nature and course of pancreatitis caused by 6-mercaptopurine in the treatment of inflammatory bowel disease. Gastroenterology. 1986; 91:982-6. [PubMed 2427386]

134. Lichtenstein GR, Abreu MT, Cohen R et al. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006; 130:935-9. [PubMed 16530531]

135. US Food and Drug Administration. FDA drug safety communication: Safety review update on reports of hepatosplenic T-cell lymphoma in adolescents and young adults receiving tumor necrosis factor (TNF) blockers, azathioprine and/or mercaptopurine. Rockville, MD; 2011 Apr 14. From FDA website. Accessed 2011 Jul 26.

a. AHFS drug information 2005. McEvoy GK, ed. Mercaptopurine. Bethesda, MD: American Society of Health-System Pharmacists; 2009:1104-6.

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