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Mercaptopurine

Pronunciation

Pronunciation: mer-KAP-toe-PURE-een
Class: Purine analog

Trade Names

Purinethol
- Tablets, oral 50 mg

Pharmacology

Mercaptopurine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase and is converted to thioinosinic acid (TIMP). This intracellular nucleotide inhibits several reactions involving inosinic acid (IMP). In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP inhibit de novo purine ribonucleotide synthesis.

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Pharmacokinetics

Absorption

Absorption is incomplete and variable, averaging 50%.

Distribution

Protein binding is approximately 19% (over concentration of 10 to 50 mcg/mL). Entry into CSF is negligible.

Metabolism

The major pathways for metabolism are hepatic via methylation and oxidation.

Elimination

46% of the dose is excreted in urine within 24 h as parent drug and metabolites. Plasma half-life is 47 min in adults.

Special Populations

Renal Function Impairment

Might result in slower elimination of the drug and metabolites, and a greater cumulative effect.

Children

Plasma half-life is 21 minutes.

Indications and Usage

For maintenance therapy of acute lymphatic (lymphocytic, lymphoblastic) leukemia as part of a combination regimen.

Unlabeled Uses

Non-Hodgkin lymphoma, Crohn disease, ulcerative colitis.

Contraindications

Prior resistance to this drug; hypersensitivity to the drug or any component of this formulation.

Dosage and Administration

Acute Lymphatic Leukemia
Adults and Children

PO For remission induction, the dosage is 2.5 mg/kg/day, rounded to the nearest multiple of 25 mg. If after 4 weeks at the initial dosage there is no clinical improvement and no definite evidence of leukocyte or platelet depression, the dosage may be increased up to 5 mg/kg daily. Maintenance dosage is 1.5 to 2.5 mg/kg/day as a single dose. Once a complete hematologic remission is obtained, maintenance therapy is considered essential. It is to be emphasized that in children with acute lymphatic leukemia in remission, superior results have been obtained when mercaptopurine has been combined with other agents (most frequently with methotrexate) for remission maintenance. Mercaptopurine should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia.

Alternative dosage
Adults

PO Initiate therapy with 80 to 100 mg/m 2 /day, rounded to the nearest 25 mg.

Children Induction therapy

PO 70 to 100 mg/m 2 /day, rounded to the nearest 25 mg.

Maintenance therapy

PO 75 mg/m 2 /day, rounded to the nearest 25 mg.

Concomitant allopurinol therapy

When allopurinol and mercaptopurine are coadministered, the dose of mercaptopurine must be reduced to one-third to one-fourth of the usual dose.

Renal function impairment

For CrCl less than 50 mL/min, hemodialysis, continuous ambulatory peritoneal dialysis, or continuous renal replacement therapy, administer every 48 h.

Hepatic function impairment

Consider reducing the dose.

General Advice

  • For oral use. Should be taken on an empty stomach.
  • Risk of relapse may be lower with evening administration than with morning administration.
  • For mercaptopurine 50 mg/mL oral suspension, crush thirty 50 mg oral tablets completely. Combine with 1:1 mixture of methylcellulose 1% and syrup to form a paste. Dilute with sufficient amount of methylcellulose/syrup mixture for a final total volume of 30 mL. Simple syrup or cherry syrup may be used. Shake suspension well before using. Compounded suspension is stable for 14 days at room temperature in amber glass bottles.
  • Renal adverse reactions can be minimized by increasing hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase inhibitor (eg, allopurinol).

Storage/Stability

Store between 59° and 77°F in a dry place.

Drug Interactions

Allopurinol

Inhibition of mercaptopurine metabolism; coadministration may cause increased severe toxicity (eg, bone marrow toxicity). Reduce dose of mercaptopurine to one-third to one-fourth of the usual dose.

Aminosalicylates (eg, mesalazine, olsalazine, sulfasalazine)

Bone marrow toxicity may be exacerbated by concomitant use of these agents. Coadminister with caution.

Azathioprine

The risk of myelosuppression may be increased as a result of additive bone marrow suppression. Avoid coadministration.

Febuxostat

Mercaptopurine plasma concentrations may be elevated, increasing the risk of toxicity. Coadministration is contraindicated.

Hydantoins (eg, phenytoin)

Hydantoin plasma concentrations and therapeutic effectiveness may be reduced. Seizure frequency may be increased. Larger hydantoin doses may be needed during coadministration of mercaptopurine. Monitor phenytoin plasma concentrations, seizure frequency, and hydantoins toxicity during and after mercaptopurine treatment and adjust the hydantoin dose as needed.

Nondepolarizing muscle relaxants (eg, tubocurarine)

The pharmacological effect of nondepolarizing muscle relaxants may be decreased or reversed. Close monitoring of respiratory function is critical. Nondepolarizing muscle relaxant dosage adjustments may be necessary with combination therapy.

Palifermin

Coadministration within the same 24-h time period may increase the severity and duration of oral mucositis. Palifermin should not be administered within 24 h before, during, or 24 h after administration of mercaptopurine.

Ribavirin

The risk of mercaptopurine-related myelosuppression (eg, pancytopenia) may be increased. If coadministration of these agents cannot be avoided, closely monitor for myelotoxicity. Be prepared to discontinue one or both agents.

Trimethoprim-sulfamethoxazole

Potentiates bone marrow suppression associated with mercaptopurine. Mercaptopurine dosage adjustment may be needed.

Vaccines, live

Induction of immunity to vaccines may be reduced, depending on the mercaptopurine dose and temporal association to drug administration. In addition, the risk of live vaccine induced adverse reactions may be increased by coadministration of mercaptopurine. Defer the use of live vaccines in patients receiving mercaptopurine.

Warfarin

Mercaptopurine may decrease the hypoprothrombinemic effect of warfarin; monitor anticoagulant activity and adjust warfarin therapy as necessary.

Adverse Reactions

Dermatologic

Alopecia; hyperpigmentation; rash.

GI

Anorexia; intestinal ulceration; mild diarrhea; nausea; oral lesions resembling thrush; sprue-like symptoms; vomiting.

Genitourinary

Hyperuricemia; hyperuricosuria; oligospermia.

Hematologic

Myelosuppression (eg, anemia, leukopenia, thrombocytopenia).

Miscellaneous

Hepatotoxicity; drug fever.

Precautions

Monitor

It is recommended that evaluation of the Hgb or Hct, total WBC count and differential count, and quantitative platelet count be obtained weekly while the patient is on therapy. In cases in which the cause of fluctuations in the formed elements in the peripheral blood is obscure, bone marrow examination may be useful for the evaluation of marrow status. The decision to increase, decrease, continue, or discontinue a given dosage must be based not only on the absolute hematologic values, but also upon the rapidity with which changes are occurring. In many instances, particularly during the induction phase of acute leukemia, CBCs will need to be done more frequently than once weekly in order to evaluate the effect of the therapy. If a patient has clinical or laboratory evidence of severe bone marrow toxicity, particularly myelosuppression, consider thiopurine-S-methyltransferase (TPMT) testing. Monitor serum transaminases, alkaline phosphatase, and bilirubin at weekly intervals when beginning therapy and at monthly intervals thereafter.


Pregnancy

Category D . May cause fetal harm.

Lactation

Undetermined.

Elderly

Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy. Start at the low end of the dosing range.

Renal Function

Start with smaller doses because of the possibility of slower drug elimination and a greater cumulative effect in patients with renal impairment.

Hepatic Function

Start with smaller doses because of the possibility of slower drug elimination and a greater cumulative effect in patients with hepatic impairment.

Bone marrow toxicity

Most consistent dose-related toxicity is bone marrow suppression manifested by anemia, leukopenia, or thrombocytopenia, or any combination of these.

Enzyme deficiency

There are patients with inherent deficiency of the enzyme TPMT who may be unusually sensitive to the myelosuppressive effects of mercaptopurine and prone to developing rapid bone marrow suppression.

Hepatotoxicity

Hepatotoxicity occurs with greatest frequency when dosages of 2.5 mg/kg/day are exceeded. Deaths have occurred from hepatic necrosis.

Immunosuppression

Induction of immunity to infectious agents or vaccines will be subnormal in patients receiving mercaptopurine. Carefully consider effect with regard to intercurrent infections and risk of subsequent neoplasm.

Resistance

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

Overdosage

Symptoms

Anorexia, diarrhea, gastroenteritis, liver dysfunction, myelosuppression, nausea, vomiting.

Patient Information

  • Advise patient, family, or caregiver that medication may be used in combination with other agents to achieve max benefit possible.
  • Advise patient that the risk of relapse may be lower with evening administration than with morning administration.
  • Advise patient, family, or caregiver to immediately report any of the following to health care provider: rash; hives; difficulty breathing; fever, chills, or other signs of infection; bleeding or unusual bruising; sores in the mouth; dark urine; yellowing of the skin or eyes.
  • Advise patient, family, or caregiver to report any of the following to health care provider: persistent nausea, vomiting, diarrhea, or appetite loss; persistent or worsening general body weakness.
  • Advise women of childbearing potential to avoid becoming pregnant during therapy.

Copyright © 2009 Wolters Kluwer Health.

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