Purinethol

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, 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. 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 DOSAGE AND ADMINISTRATION).

Bone marrow toxicity may be more profound in patients treated with concomitant allopurinol (see PRECAUTIONS, Drug Interactions and DOSAGE AND ADMINISTRATION). 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.

Mercaptopurine recipients may manifest decreased cellular hypersensitivities and decreased allograft rejection. Induction of immunity to infectious agents or vaccines will be subnormal in these patients; the degree of immunosuppression will depend on antigen dose and temporal relationship to drug. This immunosuppressive effect should be carefully considered with regard to intercurrent infections and risk of subsequent neoplasia.