Purinethol

Generic Name: Mercaptopurine
Class: Antineoplastic Agents
VA Class: AN300
CAS Number: 6112-76-1

Introduction

Antineoplastic and immunosuppressive agent; purine antagonist.^{a 103}

Uses for Purinethol

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.)

Purinethol 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 Purinethol

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 Purinethol

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

Purinethol 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 02/2013. 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