Purinethol Information
Purinethol (Mercaptopurine) 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 (Mercaptopurine) and knowledgeable in assessing response to chemotherapy.
Purinethol (Mercaptopurine) Description
Purinethol (Mercaptopurine) was synthesized and developed by Hitchings, Elion, and associates at the Wellcome Research Laboratories.
Mercaptopurine, known chemically as 1,7-dihydro-6-purine-6-thione monohydrate, is an analogue of the purine bases adenine and hypoxanthine. Its structural formula is:
Purinethol (Mercaptopurine) 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.
Purinethol (Mercaptopurine) Clinical Pharmacology
Mercaptopurine (6-MP) competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to thioinosinic acid (TIMP). This intracellular nucleotide 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). In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine is converted 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 its metabolites are directly or predominantly responsible for cell death.
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 are unknown. 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 of distribution usually exceeded that of the total body water.
Following the oral administration of S-6-mercaptopurine in one subject, a total of 46% of the dose could be accounted for in the urine (as parent drug and metabolites) in the first 24 hours. There is negligible entry of mercaptopurine into cerebrospinal fluid.
Plasma protein binding averages 19% over the concentration range 10 to 50 mcg/mL (a concentration only achieved 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 and allopurinol (see and ).
Purinethol (Mercaptopurine) Indications And Usage
Purinethol (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).
Purinethol (Mercaptopurine) is not effective for prophylaxis or treatment of central nervous system leukemia.
Purinethol (Mercaptopurine) is not effective in acute myelogenous leukemia, chronic lymphatic leukemia, the lymphomas (including Hodgkins Disease), or solid tumors.
Purinethol (Mercaptopurine) Contraindications
Purinethol (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.
Purinethol (Mercaptopurine) should not be used in patients who have a hypersensitivity to mercaptopurine or any component of the formulation.
Purinethol (Mercaptopurine) Warnings
Mercaptopurine is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient's risk of neoplasia. Cases of hepatosplenic T-cell lymphoma have been reported in patients treated with mercaptopurine for inflammatory bowel disease. The safety and efficacy of mercaptopurine in patients with inflammatory bowel disease have not been established.
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 reflect progression of the underlying disease. In many patients with severe depression of the formed elements of the blood due to Purinethol (Mercaptopurine) , the bone marrow appears hypoplastic on aspiration or biopsy, whereas in other 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 of mercaptopurine-induced granulocytopenia and thrombocytopenia. Since mercaptopurine may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an unexpected abnormally large fall in any of the formed elements of the blood, if not attributable to another drug or disease process.
Individuals who are homozygous for an inherited defect in the TPMT (thiopurine-S-methyltransferase) gene are unusually sensitive to the myelosuppressive effects of mercaptopurine and prone to developing rapid bone marrow suppression following the initiation of treatment. Laboratory tests are available, both genotypic and phenotypic, to determine the TPMT status. Substantial dose reductions are generally required for homozygous-TPMT deficiency patients (two non-functional alleles) to avoid the development of life threatening bone marrow suppression. Although heterozygous patients with intermediate TPMT activity may have increased mercaptopurine toxicity, this is variable, and the majority of patients tolerate normal doses of Purinethol (Mercaptopurine) . If a patient has clinical or laboratory evidence of severe toxicity, particularly myelosuppression, TPMT testing should be considered. In patients who exhibit excessive myelosuppression due to 6-mercaptopurine, it may be possible to adjust the mercaptopurine dose and administer the usual dosage of other myelosuppressive chemotherapy as required for treatment (see ).
Bone marrow toxicity may be more profound in patients treated with concomitant allopurinol (see , and ). This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, or sulphasalazine.
Mercaptopurine is hepatotoxic in animals and humans. A small number of deaths have been reported that may have been attributed to hepatic necrosis due to administration of mercaptopurine. Hepatic injury can occur 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 cholestasis and parenchymal cell necrosis, either of which may predominate. It is not clear how much of the hepatic damage is due to direct toxicity from the drug and how much may be due to a hypersensitivity reaction. In some patients jaundice has cleared following withdrawal of mercaptopurine and reappeared with its reintroduction.
Published reports have cited widely varying incidences of overt hepatotoxicity. In a large series of patients with various neoplastic diseases, mercaptopurine was administered orally in doses ranging from 2.5 mg/kg to 5.0 mg/kg without evidence of hepatotoxicity. It was noted by the authors that no definite clinical evidence of 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 pediatric leukemic patients, the incidence of hepatotoxicity ranged from 0% to 6%. In an isolated report by Einhorn and 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 with mercaptopurine. The hepatotoxicity has been associated in some cases with anorexia, diarrhea, jaundice and ascites. Hepatic encephalopathy has occurred.
Monitoring of serum transaminase levels, alkaline phosphatase, and bilirubin levels may allow early detection of hepatotoxicity. It is advisable to monitor these liver function tests at weekly intervals when first beginning therapy and at monthly intervals thereafter. Liver function tests may be advisable more frequently in patients who 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 are immediate 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 with other drugs not felt to be hepatotoxic should nevertheless be approached with caution. The combination of mercaptopurine with doxorubicin was reported to be hepatotoxic in 19 of 20 patients undergoing remission-induction therapy for leukemia resistant to previous therapy.
Purinethol (Mercaptopurine) Precautions
When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced 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 whose primary or secondary toxicity is myelosuppression. Enhanced marrow suppression has been noted in some patients also receiving trimethoprim-sulfamethoxazole.
Inhibition of the anticoagulant effect of warfarin, when given with mercaptopurine, has been reported.
As there is 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 ).
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 of mercaptopurine during pregnancy were found sterile, or if they became pregnant, had smaller litters and more dead fetuses as compared to control animals. Carcinogenic potential exists in humans, but the extent of the risk is unknown.
The effect of mercaptopurine on human fertility is unknown for either males or females.
Purinethol (Mercaptopurine) Adverse Reactions
The principal and potentially serious toxic effects of Purinethol (Mercaptopurine) are bone marrow toxicity and hepatotoxicity (see and ).
The administration of Purinethol (Mercaptopurine) has been associated with skin rashes and hyperpigmentation. Alopecia has been reported.
Drug fever has been very rarely reported with Purinethol (Mercaptopurine) . Before attributing fever to Purinethol (Mercaptopurine) , every attempt should be made to exclude more common causes of pyrexia, such as sepsis, in patients with acute leukemia.
Oligospermia has been reported.
Purinethol (Mercaptopurine) Overdosage
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 clear mercaptopurine. Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation of mercaptopurine into active metabolites with long persistence. The oral LD of mercaptopurine was determined 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 discontinued immediately if unintended toxicity occurs during treatment. If a patient is seen immediately following an accidental overdosage of the drug, it may be useful to induce emesis.
Purinethol (Mercaptopurine) Dosage And Administration
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 Purinethol (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 lymphatic leukemia in remission, superior results have been obtained when Purinethol (Mercaptopurine) has been combined with other agents (most frequently with methotrexate) for remission maintenance. Purinethol (Mercaptopurine) should rarely be 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 on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe Purinethol (Mercaptopurine) toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established. (See , , and sections.)
Most patients with heterozygous TPMT deficiency tolerated recommended Purinethol (Mercaptopurine) doses, but some require dose reduction. Genotypic and phenotypic testing of TPMT status are available. (See , , and sections.)
Purinethol (Mercaptopurine) How Supplied
Pale yellow to buff, scored tablets containing 50 mg mercaptopurine, imprinted with “Purinethol (Mercaptopurine) ” and “04A”; bottles of 60 (NDC 57844-522-06).
Purinethol (Mercaptopurine)
Purinethol (Mercaptopurine)
