SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 9 DRUG INTERACTIONS 10 DOSAGE AND ADMINISTRATION 11 OVERDOSAGE 12 ACTION AND CLINICAL PHARMACOLOGY 12 STORAGE AND STABILITY 15 SPECIAL HANDLING INSTRUCTIONS 15 DOSAGE FORMS, COMPOSITION AND PACKAGING 15
PHARMACEUTICAL INFORMATION 16 DETAILED PHARMACOLOGY 17 TOXICOLOGY 17 REFERENCES 26
PrPURINETHOL(r) Mercaptopurine Tablets USP
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Tablet 50 mg | lactose For a complete listing see Dosage Forms, Composition and Packaging section. |
PURINETHOL(r) (MERCAPTOPURINE) 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. PURINETHOL(r) (mercaptopurine) is indicated for: remission induction remission consolidation maintenance therapy of the acute leukemias. The response to this agent depends upon the particular sub-classification of the acute leukemia (lymphatic, myelogenous, undifferentiated, etc.) and the age of the patient (child or adult). PURINETHOL(r) 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 subclassifications. These results are inferior to those achieved with combination chemotherapy employing optimum treatment schedules.
Chronic Myelogenous (Granulocytic) Leukemia
Mercaptopurine is one 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.
Central Nervous System Leukemia
Mercaptopurine is not effective for prophylaxis or treatment of central nervous system leukemia.
Other Neoplasms
Mercaptopurine is not effective in chronic lymphocytic leukemia, the lymphomas (including Hodgkin's Disease), or solid tumors.
Geriatrics:
No data is available.
Pediatrics:
Acute lymphatic leukemia occurring in children responds, in general, more favorably to mercaptopurine than the same disorder occurring in adults.
Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. PURINETHOL(r) (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.
Immunization using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunizations with live organism vaccines are not recommended.
The safe and effective use of PURINETHOL(r) (mercaptopurine) 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.
Carcinogenesis and Mutagenesis
PURINETHOL(r) in common with other anti-metabolites causes chromosomal aberrations in mice, rats and man and induces dominant-lethal mutations in male mice. Carcinogenic potential exists in man, as post-marketing surveys have documented the occurrence of acute non- lyphocytic leukaemia, acute myelogenous leukaemia and chronic myeloid leukaemia in patients treated with 6-MP. These data include patients who received 6-mercaptopurine for non-neoplastic disorders.
Hematologic
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. Full blood counts must be taken daily during remission induction and careful monitoring of haematological parameters should be conducted during maintenance therapy. 6-MP is primarily metabolized by the enzyme thiopurine S-methyltransferase(TPMT), whose activity can be highly variable due to polymorphisms in the TPMT gene. Approximately 0.3% of Caucasians and African Americans have little to no enzyme due to 2 non-functional TPMT alleles (homozygous deficient). 10% of patients have only one functional allele (heterozygotes) resulting in intermediate TPMT activity, whereas approximately 90% of individuals have normal TPMT activity with two functional alleles. Patients with low or intermediate TPMT activity accumulate higher concentrations of 6-MP cytotoxic metabolites than those with normal TPMT activity. These patients may therefore be unusually sensitive to the myelosuppressive effect of 6- mercaptopurine and prone to developing profound bone marrow depression following the initiation of treatment with 6-MP. A possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has also been reported in individuals receiving 6- mercaptopurine in combination with other cytotoxics. Although available, phenotypic or genetic screening tests for TPMT deficiency are not currently uniform for patient care in Canada.
Hepatotoxicity
PURINETHOL(r) (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 2.5mg/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 pre-existing 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.
Immune
Immunization
Immunization using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunizations with live organism vaccines are not recommended.
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.
Renal
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.
Sexual Function/Reproduction
Teratogenesis
Mercaptopurine has been shown to be embryotoxic in rats at doses that are not toxic to the mother. It has also proven to be embryo-lethal when administered at higher doses in the first half of the gestation period. 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.
The effect of mercaptopurine on human fertility is unknown for either males or females, but there are reports of successful fatherhood/motherhood after receiving treatment during childhood or adolescence.
Special Populations
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised if either partner is receiving PURINETHOL(r) (see Sexual Function/Reproduction).
6-mercaptopurine has been detected in the breast milk of renal transplant patients receiving immunosuppressive therapy with azathioprine, a pro-drug of 6-mercaptopurine. Mothers receiving PURINETHOL(r) should not breast feed.
See DOSAGE AND ADMINISTRATION.
Geriatrics: No specific studies have been carried out in the elderly. However, it is advisable to monitor renal and hepatic function in these patients, and if there is any impairment, consideration should be given to reducing the PURINETHOL(r) dosage.
Monitoring and Laboratory Tests
The most consistent dose-related toxicity is bone marrow suppression. This may be manifest by anemia, leukopenia, thrombocytopenia, or any combination of these. 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. Full blood counts must be taken daily during remission induction and careful monitoring of haematological parameters should be conducted during maintenance therapy. 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 2ug/mL after a therapeutic oral dose.
Adverse Drug Reaction Overview
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).
Neoplasms benign, malignant and unspecified (including cysts and polyps) (2-6% )
Very rare Secondary Leukaemia and myelodysplasia (see WARNINGS AND PRECAUTIONS)
Gastrointestinal (3 % )
Intestinal ulceration has been reported very rarely. 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. Rare reports of Oral Ulceration. Rare reports of pancreatitis (in the licensed indications). Common reports of pancreatitis in the Inflammatory bowl disease (IBD) population (an unlicensed indication).
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.
Immune system disorders (2 - 2.7%)
Hypersensitivity reactions with the following manifestations have been reported Rare Arthralgia; skin rash, drug fever 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. Very Rare Facial oedema
Skin and subcutaneous tissue disorders (< 2%)
Rare alopecia
Miscellaneous
Transient oligospermia has been reported.
Overview
Azathioprine:
The active metabolite of azathioprine is 6-MP, which is primarily metabolized by the enzyme thiopurine S-methyltransferase (TPMT), whose activity can be highly variable due to polymorphisms in the TPMT gene. Approximately 0.3% of Caucasians and African Americans have little to no enzyme activity due to 2 non-functional TPMT alleles (homozygous deficient). 10% of patients have only one functional allele (heterozygotes) resulting in intermediate TPMT activity, whereas approximately 90% of individuals have normal TPMT activity with two functional alleles. Patients with low or intermediate TPMT activity accumulate higher concentrations of azathioprine cytotoxic metabolites than those with normal TPMT activity. These patients may therefore be unusually sensitive to the myelosuppresive effect of azathioprine and prone to developing profound bone marrow depression following the initiation of treatment with azothioprine. A possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has also been reported in individuals receiving 6-mercaptopurine in combination with other cytotoxics. Although available, phenotypic or genetic screening tests for TPMT deficiency are not currently uniform for patient care in Canada.
Allopurinol
: When allopurinol and mercaptopurine are administered concomitantly, it is imperative that the dose of mercaptopurine be reduced to 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.
Vaccinations:
Vaccination with live organism vaccines are not recommended in immunocompromised individuals (see WARNINGS AND PRECAUTIONS).
Thioguanine
: There is usually complete cross-resistance between mercaptopurine and thioguanine. The dosage of 6-mercaptopurine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression.
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.
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 AND PRECAUTIONS).
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Dosing Considerations
PURINETHOL(r) (mercaptopurine) is 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 2.5mg/kg of body weight per day or 50 to 75mg/m2 body surface area per day (100 to 200mg in the average adult and 50mg 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 5mg/kg daily. A dosage of 2.5mg/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 25mg. Studies in pediatric patients with acute lymphoblastic leukemia suggest that the administration of PURINETHOL(r) in the evening compared to the morning lowered the risk of relapse. 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.
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 2.5mg/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.
Recommended Dose and Dosage Adjustment
Dosage in the Elderly
No specific studies have been carried out in the elderly. However, it is advisable to monitor renal and hepatic function in these patients, and if there is any impairment, consideration should be given to reducing the PURINETHOL(r) dosage.
Missed Dose
If a dose is missed, the patient should be instructed to take their next dose as scheduled. Doses should not be doubled.
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. Active measures (such as the use of activated charcoal or gastric lavage) may not be effective in the event of overdose unless the procedure can be undertaken within 60 minutes of ingestion. 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.
Mechanism of Action
6-mercaptopurine is sulphydryl analogue of the purine base hypoxanthine and acts as a cytotoxic antimetabolite. 6-mercaptopurine is an inactive pro-drug which acts as a purine antagonist but requires cellular uptake and intracellular metabolism to thioguanine nucleotides for cytotoxicity. The 6- mercaptopurine metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. The thioguanine nucleotides are also incorporatead into nucleic acids and this contributes to the cytotoxic effects of the drug. 6-mercaptopurine is converted into the active thioguanine nucleotides by the enzyme hypoxanthineguanine phosphoribosyltransferase. The conversion of 6-mercaptopurine into its active thioguanine nucleotides is a stepwise process, via thioinosinic acid. 6-mercaptopurine can also undergo methylation by the enzyme thiopurine methyltransferase to form S-methylated nucleotides, which are also cytotoxic. 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.
Pharmacodynamics
The cytotoxic effect of 6-mercaptopurine can be related to the levels of red blood cell 6- mercaptopurine derived thioguanine nucleotides, but not to the plasma 6-mercaptopurine concentration. 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 2ug/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.
Pharmacokinetics
Summary of mercaptopurine's Pharmacokinetic Parameters in the patient population
| C max | t 1/2 (min) | AUC 0 - 4 | Clearance (mL/min/m 2 ) | Volume of distribution (L/kg) | |
| Single dose mean | - | 90 +- 30 | - | 4832 +- 2562 | 0.9 |
Absorption: The bioavailability of oral 6-mercaptopurine shows considerable inter-individual variability. When administered at a dosage of 75mg/m2 to 7 patients, the bioavailability averaged 16% of the administered dose, with a range of 5 to 37%. The variable bioavailability probably results from the metabolism of a significant portion of 6-mercaptopurine during first-pass hepatic metabolism.
The mean time to peak plasma concentration is 2.2 hours with a range of 0.5 to 4 hours.
There is a negligible entry of mercaptopurine into cerebrospinal fluid. Plasma protein binding averages 19% over the concentration range 10 to 50ug/mL (a concentration only achieved by intravenous administration of mercaptopurine at doses exceeding 5 to 10mg/kg).
The catabolism of mercaptopurine and its metabolites is complex. The main method of elimination for 6-mercaptopurine is by metabolic alteration. The kidneys eliminate approximately 7% of 6-mercaptopurine unaltered within 12 hours of the drug being administered. Xanthine oxidase is the main catabolic enzyme of 6-mercaptopurine and it converts the drug into the inactive metabolite, 6-thiouric acid. This is excreted in the urine.
In man, after oral administration of 35S-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 AND PRECAUTIONS). Excretion: The elimination half-life of 6-mercaptopurine is 90 +- 30 minutes, but the active metabolites have a longer half-life. The apparent body clearance is 4832 +- 2562mL/min/m2.
Special Populations and Conditions
Pharmacokinetics in the pediatric population have not been specifically studied.
Pharmacokinetics in the geriatric population have not been specifically studied.
Pharmacokinetics based on gender have not been studied.
Pharmacokinetics based on race have not been studied.
Pharmacokinetics in individuals with hepatic insufficiency have not been studied (See WARNINGS AND PRECAUTIONS, Hepatotoxicity).
slower elimination of the drug and a greater cumulative effect (See WARNINGS AND PRECAUTIONS, Renal).
Pharmacokinetics effects due to genetic polymorphism have not been studied.
Purinethol(r) Tablets should be stored in a dry place between 15o and 25o C, protected from light.
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 1000oC 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.
Each scored tablet contains 50 mg mercaptopurine and the following non-medicinal ingredients: corn starch, lactose, magnesium stearate, potato starch and stearic acid. PURINETHOL(r) Tablets 50 mg are pale yellow to buff, scored tablets imprinted with "PURINETHOL" and "O4A". Bottles of 25.