Action And Clinical Pharmacology: Clinical studies have shown the absorption of an oral dose of mercaptopurine in man is incomplete and variable, averaging approximately 50% of the administered dose. The factors influencing absorption are unknown. I.V. administration of an investigational preparation of mercaptopurine revealed a plasma half-disappearance time of 21 minutes in children and 47 minutes in adults. The volume of distribution usually exceeded that of the total body water.
Mercaptopurine is extensively metabolized and excreted via the kidneys and the active metabolites have a longer half-life than the parent drug. Following the oral administration of 5-6-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. Metabolites of mercaptopurine were found in urine within the first 2 hours after administration. Radioactivity (in the form of sulfate) could be found in the urine for weeks afterwards. The half-life of orally administered 6-mercaptopurine in the circulation is approximately 90 minutes.
There is a negligible entry of mercaptopurine into cerebrospinal fluid.
Plasma protein binding averages 19% over the concentration range 10 to 50 g/mL (a concentration only achieved by i.v. administration of mercaptopurine at doses exceeding 5 to 10 mg/kg).
Monitoring plasma levels of mercaptopurine during therapy is of questionable value. It is technically difficult to determine plasma concentrations which are seldom greater than 1 to 2 g/mL after a therapeutic oral dose. More significantly mercaptopurine enters rapidly into the anabolic and catabolic pathways for purines and the active intracellular metabolites have appreciably longer half-lives than the parent drug. The biochemical effects of a single dose of mercaptopurine are evident long after the parent drug has disappeared from plasma. Because of this rapid metabolism of mercaptopurine to active intracellular derivatives, hemodialysis would not be expected to appreciably reduce toxicity of the drug. There is no known pharmacologic antagonist to the biochemical actions of mercaptopurine in vivo.
Azathioprine is cleaved in vivo to mercaptopurine. Mercaptopurine 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 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.
The catabolism of mercaptopurine and its metabolites is complex. In man, after oral administration of 5-6-mercaptopurine, urine contains intact mercaptopurine, thiouric acid (formed by direct oxidation by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine) and a number of 6-methylated thiopurines. The methylthiopurines yield appreciable amounts of inorganic sulfate. The importance of the metabolism by xanthine oxidase relates to the fact that allopurinol inhibits this enzyme and retards the catabolism of mercaptopurine and its active metabolites. A significant reduction in mercaptopurine dosage is mandatory if a potent xanthine oxidase inhibitor and mercaptopurine are used simultaneously in a patient (see Warnings).
Indications And Clinical Uses: For remission induction, remission consolidation, and maintenance therapy of the acute leukemias. The response to this agent depends upon the particular sub-classification of the acute leukemia (lymphatic, myelogenous, undifferentiated) and the age of the patient (child or adult). Mercaptopurine is also indicated for the palliative treatment of chronic myelogenous (granulocytic) leukemia.
Acute Lymphatic (Lymphocytic, Lymphoblastic) Leukemia: Acute lymphatic leukemia occurring in children responds, in general, more favorably to mercaptopurine than the same disorder occurring in adults. Given as a single agent for remission induction, mercaptopurine induces complete remission in approximately 25% of children and 10% of adults. These results can be improved upon considerably by using multiple, carefully selected agents in combination. Reliance upon mercaptopurine alone is seldom justified. The duration of complete remission induced in children with acute lymphatic leukemia is so brief without the use of maintenance therapy that some form of drug therapy is considered essential following remission induction. Mercaptopurine, as a single agent, is capable of significantly prolonging complete remission duration in children; however, combination therapy with multiple agents has produced results superior to that achieved with mercaptopurine alone. The effectiveness of mercaptopurine in maintenance programs in adult acute lymphatic leukemia has not been established.
Acute Myelogenous (and Acute Myelomonocytic) Leukemia: As a single agent, mercaptopurine will induce complete remission in approximately 10% of children and adults with acute myelogenous leukemia or its sub-classifications. These results are inferior to those achieved with combination chemotherapy employing optimum treatment schedules.
Chronic Myelogenous (Granulocytic) Leukemia: Mercaptopurine is 1 of several agents with demonstrated efficacy in the treatment of chronic myelogenous leukemia. Approximately 30 to 50% of patients with chronic myelogenous leukemia obtain an objective response to mercaptopurine. This is less than the 90% objective responses with busulfan, and, of these two agents, busulfan is usually regarded as the preferred drug for initial therapy.
CNS Leukemia: Mercaptopurine is not effective for prophylaxis or treatment of CNS leukemia.
Other Neoplasms: Mercaptopurine is not effective in chronic lymphatic leukemia, the lymphomas (including Hodgkin’s Disease), or solid tumors.
Contra-Indications: Mercaptopurine should not be used unless a diagnosis of acute leukemia or chronic myelogenous leukemia has been adequately established and the responsible physician is knowledgeable in assessing response to chemotherapy. Mercaptopurine should not be used in patients whose disease has demonstrated prior resistance to this drug. In animals and man there is usually complete cross-resistance between mercaptopurine and thioguanine.
Manufacturers’ Warnings In Clinical States: Caution: Purinethol is a potent drug and should be used only by physicians experienced with cancer chemotherapy drugs. Blood counts should be taken once or twice weekly. Discontinue or reduce the dosage upon evidence of abnormal depression of the bone marrow. Liver function must be evaluated prior to and at weekly intervals at the beginning of therapy and monthly thereafter.
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 indicate progression of the underlying disease. It is imperative that patients be instructed to report promptly the development of fever, sore throat, signs of local infection, bleeding from any site, or symptoms suggestive of anemia. Since mercaptopurine may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an abnormally large fall in any of the formed elements of the blood.
There are rare individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effects of mercaptopurine and prone to developing rapid bone marrow suppression following the initiation of treatment. Substantial dosage reductions may be required to avoid the development of life-threatening bone marrow suppression in these patients. This toxicity may be more profound in patients treated with concomitant allopurinol (see Warnings, Drug Interactions).
Hepatotoxicity: Mercaptopurine is hepatotoxic in animals and man; deaths have been reported from hepatic necrosis. Hepatic injury can occur with any dosage, but seems to occur with greatest 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; several reports have indicated that as many as 10 to 40% of patients with acute leukemia develop jaundice while receiving treatment with mercaptopurine.
Usually, clinically detectable jaundice appears early in the course of treatment (1 or 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.
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 preexisting liver disease.
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.
The hepatotoxicity has been associated in some cases with anorexia, diarrhea, jaundice, and ascites. Hepatic encephalopathy has occurred. 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 lead to a search for an etiology of the hepatotoxicity.
Drug Interactions: Allopurinol: When allopurinol and mercaptopurine are administered concomitantly, it is imperative that the dose of mercaptopurine be reduced one-third to one-quarter of the usual dose. Failure to observe this dosage reduction will result in a delayed catabolism of mercaptopurine and the strong likelihood of inducing severe toxicity.
Warfarin: Inhibition of the anticoagulant effect of warfarin when given with mercaptopurine has been reported.
Thioguanine: see Precautions.
Trimethoprim-Sulfamethoxazole: see Precautions.
Immunosuppression: Mercaptopurine recipients may manifest decreased cellular hypersensitivities and impaired 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 drug effect is similar to that of azathioprine and should be carefully considered with regard to intercurrent infections and risk of subsequent neoplasia.
Mutagenesis and Carcinogenesis: Mercaptopurine causes chromosomal aberrations in animals and man and induces dominant-lethal mutations in male mice. Carcinogenic potential exists in man. Cases have been documented of the occurrence of acute nonlymphatic leukemia in patients who received mercaptopurine for non-neoplastic disorders.
Teratogenesis: Mercaptopurine has embryopathic effects in rats. Women receiving mercaptopurine in the first trimester of pregnancy have an increased incidence of abortion; the risk of malformation in offspring surviving first trimester exposure is not accurately known. In a series of 28 women receiving mercaptopurine after the first trimester of pregnancy, 3 mothers died undelivered, 1 delivered a stillborn child, and 1 aborted; there were no cases of macroscopically abnormal fetuses.
Since such experience cannot exclude the possibility of fetal damage, mercaptopurine should be used during pregnancy only if the benefit clearly justifies the possible risk to the fetus, and particular caution should be given to the use of mercaptopurine in the first trimester of pregnancy.
Effects on Fertility: The effect of mercaptopurine on human fertility is unknown for either males or females.
Lactation: Mothers receiving mercaptopurine should not breast-feed.
Precautions: General: The safe and effective use demands a thorough knowledge of the natural history of the condition being treated. For example, remission induction of adult acute leukemia virtually always necessitates the production of moderate to severe bone marrow hypoplasia. The degree of myelosuppression acceptable in this disease would not be desirable in the management of chronic granulocytic leukemia. After selection of an initial dosage schedule, therapy will frequently need to be modified depending upon the patient’s response and manifestations of toxicity.
The most frequent, serious, toxic effect of mercaptopurine is myelosuppression resulting in leukopenia, thrombocytopenia and anemia. These toxic effects are often unavoidable during the induction phase of adult acute leukemia if remission induction is to be successful. Whether or not these manifestations demand modification or cessation of dosage depends both upon the response of the underlying disease and a careful consideration of supportive facilities (granulocyte and platelet transfusions) which may be available. Life-threatening infections and bleeding have been observed as a consequence of mercaptopurine induced granulocytopenia and thrombocytopenia. Severe hematologic toxicity may require supportive therapy with platelet transfusions for bleeding, and antibiotics and granulocyte transfusions if sepsis is documented.
If it is not the intent to induce bone marrow hypoplasia, it is important to discontinue the drug temporarily at the first evidence of an abnormally large fall in white blood cell count, platelet count or hemoglobin concentration as leukocyte and platelet counts continue to fall after treatment is stopped. In many patients with severe depression of the formed elements of the blood due to 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 towards the megaloblastic series, characteristically seen with the folic acid antagonists and some other antimetabolites, are not seen with this drug.
It is recommended that evaluation of the hemoglobin or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained weekly while the patient is on mercaptopurine therapy. In cases where 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 of mercaptopurine 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, complete blood counts will need to be done more frequently than once weekly (often daily) in order to evaluate the effect of the therapy. The dosage of mercaptopurine may need to be reduced when this agent is combined with other drugs whose primary toxicity is myelosuppression.
Impaired Renal Function: It is probably advisable to start with smaller dosages in patients with impaired renal function, since the latter might result in slower elimination of the drug and a greater cumulative effect.
Drug Interactions: Allopurinol: see Warnings.
Warfarin: see Warnings.
Thioguanine: There is usually complete cross-resistance between mercaptopurine and thioguanine.
Trimethoprim-Sulfamethoxazole: The dosage of mercaptopurine may need to be reduced when mercaptopurine 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.
Pregnancy: As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised if either partner is receiving mercaptopurine (see Warnings).
Adverse Reactions: Hematologic: The most frequent adverse reaction to mercaptopurine is myelosuppression. The induction of complete remission of acute lymphatic leukemia frequently is associated with marrow hypoplasia. Maintenance of remission generally involves multiple drug regimens whose component agents cause myelosuppression. Anemia, leukopenia, and thrombocytopenia are frequently observed. Dosages and schedules are adjusted to prevent life-threatening cytopenias (see Warnings and Precautions).
Gastrointestinal: Intestinal ulceration has been reported. Nausea, vomiting and anorexia are uncommon during initial administration, but they may occur during toxicity. Mild diarrhea and sprue-like symptoms have been noted occasionally, but it is difficult at present to attribute these to the medication. Oral lesions are rarely seen, and when they occur they resemble thrush rather than antifolic ulcerations.
An increased risk of pancreatitis may be associated with the investigational use of mercaptopurine in inflammatory bowel disease.
Renal: Hyperuricemia frequently occurs in patients receiving mercaptopurine as a consequence of rapid cell lysis accompanying the antineoplastic effect. Adverse effects can be minimized by increased hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase inhibitor such as allopurinol. The dosage of mercaptopurine should be reduced to one-third to one-quarter of the usual dose if allopurinol is given concurrently.
Miscellaneous: While dermatologic reactions can occur as a consequence of disease, the administration of mercaptopurine has been associated with skin rashes and hyperpigmentation.
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 with acute leukemia.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Signs and symptoms of overdosage may be immediate such as anorexia, nausea, vomiting and diarrhea; or delayed such as myelosuppression, liver dysfunction, and gastroenteritis. 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, induced emesis may be useful. 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.
Dosage And Administration: Induction and Consolidation Therapy: Administered orally. The dosage which will be tolerated or will be effective varies from patient to patient, and therefore careful titration is necessary to obtain the optimum therapeutic effect without incurring excessive, unintended toxicity. The usual initial dosage for children and adults is 2.5 mg/kg of body weight per day (100 to 200 mg in the average adult and 50 mg in an average 5-year-old child). Children with acute leukemia have tolerated this dose without difficulty in most cases; it may be continued daily for several weeks or more in some patients. If after 4 weeks at this dosage, there is no clinical improvement and no definite evidence of leukocyte or platelet depression, the dosage may be increased by up to 5 mg/kg daily.
A dosage of 2.5 mg/kg per day may result in a rapid fall in leukocyte count within 1 to 2 weeks in some adults with acute leukemia and high total leukocyte counts, as well as in certain adults with chronic myelocytic leukemia.
The total daily dosage may be given at one time. It is calculated to the nearest multiple of 25 mg. The dosage of mercaptopurine should be reduced to one-third to one-quarter of the usual dose if allopurinol is given concurrently. Since the drug may have a delayed action, it should be discontinued at the first sign of an abnormally large or rapid fall in the leukocyte or platelet count. If subsequently the leukocyte count or platelet count remains constant for 2 or 3 days, or rises, treatment may be resumed.
Maintenance Therapy: If a complete hematologic remission is obtained with mercaptopurine either alone or in combination with other agents, maintenance therapy should be considered. This is indicated in children with acute lymphatic leukemia. The use of mercaptopurine in maintenance schedules for adults with acute leukemia has not been established to be effective. If remission is achieved, maintenance doses will vary from patient to patient. A 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 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.
Special Instructions: Tablets should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport.
All materials which have come in contact with cytotoxic drugs should be segregated and incinerated at 1 000°C or more. Sealed containers may explode.
Personnel regularly involved in the preparation and handling of cytotoxic agents should have bi-annual blood examinations.
Care should be taken when handling or halving the tablets so as not to contaminate hands or to inhale the drug.
Availability And Storage: Each pale yellow to buff, scored tablet, imprinted with “PURINETHOL” and “O4A”, contains: mercaptopurine 50 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate, potato starch and stearic acid. Bottles of 25. Store in a dry place between 15 and 25°C, protected from light. (Shown in Product Recognition Section)
PURINETHOL® Glaxo Wellcome Mercaptopurine Antileukemic