Slideshows Images Quizzes

Copyright © 2018 by RxList Inc. RxList does not provide medical advice, diagnosis or treatment. See additional information.

Purinethol

Last reviewed on RxList: 9/17/2018
Drug Description

PURINETHOL®
(mercaptopurine) 50-mg Scored Tablets

CAUTION

PURINETHOL (mercaptopurine) is a potent drug. It should not be used unless a diagnosis of acute lymphatic leukemia has been adequately established and the responsible physician is experienced with the risks of PURINETHOL and knowledgeable in assessing response to chemotherapy.

DESCRIPTION

PURINETHOL (mercaptopurine) was synthesized and developed by Hitchings, Elion, and associates at the Wellcome Research Laboratories.

Mercaptopurine, known chemically as l,7-dihydro-6H-purine-6-thione monohydrate, is an analogue of the purine bases adenine and hypoxanthine. Its structural formula is:

PURINETHOL® 
  (mercaptopurine) Structural Formula Illustration

PURINETHOL is available in tablet form for oral administration. Each scored tablet contains 50 mg mercaptopurine and the inactive ingredients corn and potato starch, lactose, magnesium stearate, and stearic acid.

Indications & Dosage

INDICATIONS

Mercaptopurine is indicated for maintenance therapy of acute lymphatic (lymphocytic, lymphoblastic)leukemia as part of a combination regimen. The response to this agent depends upon the particular subclassification of acute lymphatic leukemia and the age of the patient (pediatric or adult).

Mercaptopurine is not effective for prophylaxis or treatment of central nervous system leukemia.

Mercaptopurine is not effective in acute myelogenous leukemia, chronic lymphatic leukemia, the lymphomas(including Hodgkins Disease), or solid tumors.

DOSAGE AND ADMINISTRATION

Maintenance Therapy

Once a complete hematologic remission is obtained, maintenance therapy is considered essential.Maintenance doses will vary from patient to patient. The usual daily maintenance dose of mercaptopurine is 1.5 to 2.5 mg/kg/day as a single dose. It is to be emphasized that in pediatric patients with acute lymphaticleukemia in remission, superior results have been obtained when mercaptopurine has been combined withother agents (most frequently with methotrexate) for remission maintenance. Mercaptopurine should rarelybe relied upon as a single agent for the maintenance of remissions induced in acute leukemia.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines onthis subject have been published. 1-8 There is no general agreement that all of the procedures recommendedin the guidelines are necessary or appropriate.

Dosage With Concomitant Allopurinol

When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must bereduced to one-third to one-quarter of the usual dose to avoid severe toxicity.

Dosage In Patients With TPMT And/Or NUDT15 Deficiency

Homozygous Deficiency In Either TPMT Or NUDT15

Patients with homozygous deficiency of either enzyme typically require 10% or less of the standard PURIXAN dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency.

Heterozygous Deficiency In TPMT And/Or NUDT15

Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15deficiency tolerate recommended mercaptopurine doses, but some require dose reduction based ontoxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions.

Dosage In Renal And Hepatic Impairment

It is probably advisable to start with lower dosages in patients with impaired renal function, due to slowerelimination of the drug and metabolites and a greater cumulative effect. Consideration should be given to reducing the dosage in patients with impaired hepatic function.

HOW SUPPLIED

Pale yellow to buff, scored tablets containing 50 mg mercaptopurine, imprinted with “9|3”; bottles of 25 (NDC 69076-913-02) and bottles of 250 (NDC 69076-913-25).

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Store in a dry place. Dispense in tight container as defined in the USP.

REFERENCES

1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice.Pittsburgh, PA: Oncology Nursing Society;1999:32-41.

2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division ofSafety; Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health;1992. US Dept of Health and Human Services. Public Health Service publication NIH 92-2621.

3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591.

4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987.Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. MassachusettsCollege of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.

5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling ofantineoplastic agents. Med J Australia. 1983;1:426-428.

6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clinicians. 1983;33:258-263.

7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic andhazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.

8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685.

Manufactured for: Quinn Pharmaceuticals, LLC Coral Springs, FL. Revised: May 2018

Side Effects

SIDE EFFECTS

The principal and potentially serious toxic effects of mercaptopurine are bone marrow toxicity and hepatotoxicity (see WARNINGS and PRECAUTIONS).

Hematologic

The most frequent adverse reaction to mercaptopurine is myelosuppression. The induction of completeremission of acute lymphatic leukemia frequently is associated with marrow hypoplasia. Patients without TPMT enzyme activity (homozygous-deficient) are particularly susceptible to hematologic toxicity, and somepatients with low or intermediate TPMT enzyme activity are more susceptible to hematologic toxicity thanpatients with normal TPMT activity (see WARNINGS: Bone Marrow Toxicity), although the latter can alsoexperience severe toxicity. Maintenance of remission generally involves multiple-drug regimens whose component agents cause myelosuppression. Anemia, leukopenia, and thrombocytopenia are frequentlyobserved. Dosages and also schedules are adjusted to prevent life-threatening cytopenias.

Renal

Hyperuricemia and/or hyperuricosuria may occur in patients receiving mercaptopurine as a consequence ofrapid cell lysis accompanying the antineoplastic effect. Renal adverse effects can be minimized by increased hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase inhibitor such asallopurinol. The dosage of mercaptopurine should be reduced to one third to one quarter of the usual dose ifallopurinol is given concurrently.

Gastrointestinal

Intestinal ulceration has been reported. Nausea, vomiting, and anorexia are uncommon during initialadministration, but may increase with continued administration. Mild diarrhea and sprue-like symptoms have been noted occasionally, but it is difficult at present to attribute these to the medication. Oral lesions arerarely seen, and when they occur they resemble thrush rather than antifolic ulcerations.

Miscellaneous

The administration of mercaptopurine has been associated with skin rashes and hyperpigmentation. Alopecia has been reported.

Drug fever has been very rarely reported with mercaptopurine. Before attributing fever to mercaptopurine,every attempt should be made to exclude more common causes of pyrexia, such as sepsis, in patients withacute leukemia.

Oligospermia has been reported.

Drug Interactions

DRUG INTERACTIONS

When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must bereduced to one third to one quarter of the usual dose to avoid severe toxicity.

There is usually complete cross-resistance between mercaptopurine and thioguanine.

The dosage of mercaptopurine may need to be reduced when this agent is combined with other drugs whoseprimary or secondary toxicity is myelosuppression. Enhanced marrow suppression has been noted in somepatients also receiving trimethoprim-sulfamethoxazole.

Inhibition of the anticoagulant effect of warfarin, when given with mercaptopurine, has been reported.

As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine)inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent mercaptopurine therapy (see WARNINGS).

Warnings

WARNINGS

Mercaptopurine is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient'srisk of neoplasia. Cases of hepatosplenic T-cell lymphoma have been reported in patients treated withmercaptopurine for inflammatory bowel disease. The safety and efficacy of mercaptopurine in patients withinflammatory bowel disease have not been established.

Bone Marrow Toxicity

The most consistent, dose-related toxicity is bone marrow suppression. This may be manifest by anemia,leukopenia, thrombocytopenia, or any combination of these. Any of these findings may also reflectprogression of the underlying disease. In many patients with severe depression of the formed elements of theblood due to mercaptopurine, the bone marrow appears hypoplastic on aspiration or biopsy, whereas inother cases it may appear normocellular. The qualitative changes in the erythroid elements toward the megaloblastic series, characteristically seen with the folic acid antagonists and some other antimetabolites,are not seen with this drug. Life-threatening infections and bleeding have been observed as a consequence ofmercaptopurine-induced granulocytopenia and thrombocytopenia. Since mercaptopurine may have a delayedeffect, it is important to withdraw the medication temporarily at the first sign of an unexpected abnormallylarge fall in any of the formed elements of the blood, if not attributable to another drug or disease process.

Evaluate patients with repeated severe myelosuppression for thiopurine S-methyltransferase (TPMT) ornucleotide diphosphatase (NUDT15) deficiency. TPMT genotyping or phenotyping (red blood cell TPMTactivity) and NUDT15 genotyping can identify patients who have reduced activity of these enzymes. Patientswith homozygous TPMT or NUDT15 deficiency require substantial dosage reductions.

Bone marrow toxicity may be more profound in patients treated with concomitant allopurinol (see DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION). This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, orsulphasalazine.

Hepatotoxicity

Mercaptopurine is hepatotoxic in animals and humans. A small number of deaths have been reported thatmay have been attributed to hepatic necrosis due to administration of mercaptopurine. Hepatic injury canoccur with any dosage, but seems to occur with more frequency when doses of 2.5 mg/kg/day are exceeded.The histologic pattern of mercaptopurine hepatotoxicity includes features of both intrahepatic cholestasisand parenchymal cell necrosis, either of which may predominate. It is not clear how much of the hepaticdamage is due to direct toxicity from the drug and how much may be due to a hypersensitivity reaction. Insome patients jaundice has cleared following withdrawal of mercaptopurine and reappeared with itsreintroduction.

Published reports have cited widely varying incidences of overt hepatotoxicity. In a large series of patientswith various neoplastic diseases, mercaptopurine was administered orally in doses ranging from 2.5 mg/kgto 5.0 mg/kg without evidence of hepatotoxicity. It was noted by the authors that no definite clinical evidenceof liver damage could be ascribed to the drug, although an occasional case of serum hepatitis did occur in patients receiving 6-MP who previously had transfusions. In reports of smaller cohorts of adult and pediatricleukemic patients, the incidence of hepatotoxicity ranged from 0% to 6%. In an isolated report by Einhornand Davidsohn, jaundice was observed more frequently (40%), especially when doses exceeded 2.5 mg/kg.Usually, clinically detectable jaundice appears early in the course of treatment (1 to 2 months). However,jaundice has been reported as early as 1 week and as late as 8 years after the start of treatment withmercaptopurine. The hepatotoxicity has been associated in some cases with anorexia, diarrhea, jaundice andascites. Hepatic encephalopathy has occurred.

Monitoring of serum transaminase levels, alkaline phosphatase, and bilirubin levels may allow early detectionof hepatotoxicity. It is advisable to monitor these liver function tests at weekly intervals when first beginningtherapy and at monthly intervals thereafter. Liver function tests may be advisable more frequently in patientswho are receiving mercaptopurine with other hepatotoxic drugs or with known pre-existing liver disease.The onset of clinical jaundice, hepatomegaly, or anorexia with tenderness in the right hypochondrium areimmediate indications for withholding mercaptopurine until the exact etiology can be identified. Likewise,any evidence of deterioration in liver function studies, toxic hepatitis, or biliary stasis should prompt discontinuation of the drug and a search for an etiology of the hepatotoxicity.

The concomitant administration of mercaptopurine with other hepatotoxic agents requires especially careful clinical and biochemical monitoring of hepatic function. Combination therapy involving mercaptopurine withother drugs not felt to be hepatotoxic should nevertheless be approached with caution. The combination ofmercaptopurine with doxorubicin was reported to be hepatotoxic in 19 of 20 patients undergoing remission-induction therapy for leukemia resistant to previous therapy.

Immunosuppression

Mercaptopurine recipients may manifest decreased cellular hypersensitivities and decreased allograftrejection. Induction of immunity to infectious agents or vaccines will be subnormal in these patients; thedegree of immunosuppression will depend on antigen dose and temporal relationship to drug. Thisimmunosuppressive effect should be carefully considered with regard to intercurrent infections and risk ofsubsequent neoplasia.

Pregnancy

Pregnancy Category D

Mercaptopurine can cause fetal harm when administered to a pregnant woman. Women receivingmercaptopurine in the first trimester of pregnancy have an increased incidence of abortion; the risk ofmalformation in offspring surviving first trimester exposure is not accurately known. In a series of 28 womenreceiving mercaptopurine after the first trimester of pregnancy, 3 mothers died undelivered, 1 delivered astillborn child, and 1 aborted; there were no cases of macroscopically abnormal fetuses. Since suchexperience cannot exclude the possibility of fetal damage, mercaptopurine should be used during pregnancyonly if the benefit clearly justifies the possible risk to the fetus, and particular caution should be given to theuse of mercaptopurine in the first trimester of pregnancy.

There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancyor if the patient becomes pregnant while taking the drug, the patient should be apprised of the potentialhazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Precautions

PRECAUTIONS

General

The safe and effective use of mercaptopurine demands close monitoring of the CBC and patient clinical status.After selection of an initial dosage schedule, therapy will frequently need to be modified depending upon thepatient’s response and manifestations of toxicity. It is probably advisable to start with lower dosages inpatients with impaired renal function, due to slower elimination of the drug and metabolites and a greatercumulative effect.

Laboratory Tests

(Also see WARNINGS: Bone Marrow Toxicity.) It is recommended that evaluation of the hemoglobin orhematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained weekly while the patient is on therapy with mercaptopurine. Bone marrow examination may also be usefulfor the evaluation of marrow status. The decision to increase, decrease, continue, or discontinue a givendosage of mercaptopurine must be based upon the degree of severity and rapidity with which changes areoccurring. In many instances, particularly during the induction phase of acute leukemia, complete bloodcounts will need to be done more frequently than once weekly in order to evaluate the effect of the therapy.Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicitiesor repeated episodes of myelosuppression.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Mercaptopurine causes chromosomal aberrations in animals and humans and induces dominant-lethal mutations in male mice. In mice, surviving female offspring of mothers who received chronic low doses ofmercaptopurine during pregnancy were found sterile, or if they became pregnant, had smaller litters andmore dead fetuses as compared to control animals. Carcinogenic potential exists in humans, but the extent ofthe risk is unknown.

The effect of mercaptopurine on human fertility is unknown for either males or females.

Pregnancy

Teratogenic Effects

Pregnancy Category D

See WARNINGS section.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from mercaptopurine, adecision should be made whether to discontinue nursing or to discontinue the drug, taking into account theimportance of the drug to the mother.

Pediatric Use

See DOSAGE AND ADMINISTRATION section.

Geriatric Use

Clinical studies of mercaptopurine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience hasnot identified differences in responses between the elderly and younger patients. In general, dose selectionfor an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting thegreater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drugtherapy.

Overdosage & Contraindications

OVERDOSE

Signs and symptoms of overdosage may be immediate (anorexia, nausea, vomiting, and diarrhea); or delayed(myelosuppression, liver dysfunction, and gastroenteritis). Dialysis cannot be expected to clearmercaptopurine. Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation ofmercaptopurine into active metabolites with long persistence. The oral LD50 of mercaptopurine wasdetermined to be 480 mg/kg in the mouse and 425 mg/kg in the rat.

There is no known pharmacologic antagonist of mercaptopurine. The drug should be discontinuedimmediately if unintended toxicity occurs during treatment. If a patient is seen immediately following anaccidental overdosage of the drug, it may be useful to induce emesis.

CONTRAINDICATIONS

Mercaptopurine should not be used in patients whose disease has demonstrated prior resistance to this drug.In animals and humans, there is usually complete cross-resistance between mercaptopurine and thioguanine.

Mercaptopurine should not be used in patients who have a hypersensitivity to mercaptopurine or anycomponent of the formulation.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

Mercaptopurine (6-MP) competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to thioinosinic acid (TIMP). This intracellularnucleotide inhibits several reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). Inaddition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP havebeen reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzymeunique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeledmercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine isconverted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of inosinate (IMP)dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP).

Animal tumors that are resistant to mercaptopurine often have lost the ability to convert mercaptopurine to TIMP. However, it is clear that resistance to mercaptopurine may be acquired by other means as well,particularly in human leukemias.

It is not known exactly which of any one or more of the biochemical effects of mercaptopurine and itsmetabolites are directly or predominantly responsible for cell death.

Pharmacokinetics

Clinical studies have shown that the absorption of an oral dose of mercaptopurine in humans is incomplete and variable, averaging approximately 50% of the administered dose. The factors influencing absorption areunknown. Intravenous administration of an investigational preparation of mercaptopurine revealed a plasma half-disappearance time of 21 minutes in pediatric patients and 47 minutes in adults. The volume ofdistribution usually exceeded that of the total body water.

Following the oral administration of 35S-6-mercaptopurine in one subject, a total of 46% of the dose could beaccounted for in the urine (as parent drug and metabolites) in the first 24 hours. There is negligible entry ofmercaptopurine into cerebrospinal fluid.

Plasma protein binding averages 19% over the concentration range 10 to 50 mcg/mL (a concentration onlyachieved by intravenous administration of mercaptopurine at doses exceeding 5 to 10 mg/kg).

A reduction in mercaptopurine dosage is required if patients are receiving both mercaptopurine andallopurinol (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Metabolism And Genetic Polymorphism

Several published studies indicate that patients with reduced TPMT or NUDT15 activity receiving usual dosesof mercaptopurine, accumulate excessive cellular concentrations of active 6-TGNs, and are at higher risk forsevere myelosuppression. In a study of 1028 children with ALL, the approximate tolerated mercaptopurinedosage range for patients with TPMT and/or NUDT15 deficiency on mercaptopurine maintenance therapy (asa percentage of the planned dosage) was as follows: heterozygous for either TPMT or NUDT15, 50-90%; heterozygous for both TPMT and NUDT15, 30-50%; homozygous for either TPMT or NUDT15, 5-10%.

Approximately 0.3% (1:300) of patients of European or African ancestry have two loss-of-function alleles ofthe TPMT gene and have little or no TPMT activity (homozygous deficient or poor metabolizers), and approximately 10% of patients have one loss-of-function TPMT allele leading to intermediate TPMT activity(heterozygous deficient or intermediate metabolizers). The TPMT*2, TPMT*3A, and TPMT*3C alleles accountfor about 95% of individuals with reduced levels of TPMT activity. NUDT15 deficiency is detected in <1% ofpatients of European or African ancestry. Among patients of East Asian ancestry (i.e., Chinese, Japanese,Vietnamese), 2% have two loss-of-function alleles of the NUDT15 gene, and approximately 21% have oneloss-of-function allele. The p.R139C variant of NUDT15 (present on the *2 and *3 alleles) is the most commonly observed, but other less common loss-of-function NUDT15 alleles have been observed.

Consider all clinical information when interpreting results from phenotypic testing used to determine the level of thiopurine nucleotides or TPMT activity in erythrocytes, since some coadministered drugs caninfluence measurement of TPMT activity in blood, and blood from recent transfusions will misrepresent apatient’s actual TPMT activity.

Medication Guide

PATIENT INFORMATION

Patients should be informed that the major toxicities of mercaptopurine are related to myelosuppression,hepatotoxicity, and gastrointestinal toxicity. Patients should never be allowed to take the drug without medical supervision and should be advised to consult their physician if they experience fever, sore throat,jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia.Women of childbearing potential should be advised to avoid becoming pregnant.

FDA Logo

Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

Health Solutions From Our Sponsors