MERCAPTOPURINE
DESCRIPTION:
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 KNOWLEDGEABLE IN ASSESSING RESPONSE TO
CHEMOTHERAPY.
PURINETHOL (mercaptoupurine) was synthesized and developed by Hitchings, Elion,
and associates at the Wellcome Research Laboratories. (REF. 1) It is one of a
large series of purine analogues which interfere with nucleic acid biosynthesis
and has been found active against human leukemias.
Mercaptopurine, known chemically as 1,7-dihydro- 6H-purine-6-thione monohydrate,
is an analogue of the purine bases adenine and hypoxanthine.
PURINETHOL 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.
ACTIONS/CLINICAL PHARMACOLOGY:
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. (REF. 2) 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. (REF. 2)
Following the oral administration of 35S- 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. (REF. 3)
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). (REF. 2)
Monitoring of plasma levels of mercaptopurine during therapy is of questionable
value. (REF. 3) There is technical difficulty in determining plasma
concentrations which are seldom greater than 1 to 2 mcg/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.
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. (REF. 3)
Experiments indicate that radiolabeled mercaptopurine may be recovered from the
DNA in the form of deoxythioguanosine. (REF. 4) 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. (REF. 5)
The catabolism of mercaptopurine and its metabolites is complex. 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. (REF. 3) The importance of the metabolism by xanthine oxidase relates
to the fact that ZYLOPRIM(R) (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 PRECAUTIONS).
INDICATIONS AND USAGE:
PURINETHOL (mercaptopurine) is indicated for remission induction and maintenance
therapy of acute lymphatic leukemia. The response to this agent depends upon the
particular subclassification of acute lymphatic leukemia and the age of the
patient (pediatric patients or adult).
ACUTE LYMPHATIC (LYMPHOCYTIC, LYMPHOBLASTIC) LEUKEMIA: Given as a single agent
for remission induction, PURINETHOL induces complete remission in approximately
25% of pediatric patients and 10% of adults. However, reliance upon PURINETHOL
alone is not justified for initial remission induction of acute lymphatic
leukemia since combination chemotherapy with vincristine, prednisone, and L-
asparaginase results in more frequent complete remission induction than with
PURINETHOL alone or in combination. The duration of complete remission induced
in acute lymphatic leukemia is so brief without the use of maintenance therapy
that some form of drug therapy is considered essential. PURINETHOL, as a single
agent, is capable of significantly prolonging complete remission duration;
however, combination therapy has produced remission duration longer than that
achieved with PURINETHOL alone.
ACUTE MYELOGENOUS (AND ACUTE MYELOMONOCYTIC) LEUKEMIA: As a single agent,
PURINETHOL will induce complete remission in approximately 10% of pediatric
patients and adults with acute myelogenous leukemia or its subclassifications.
These results are inferior to those achieved with combination chemotherapy
employing optimum treatment schedules.
CENTRAL NERVOUS SYSTEM LEUKEMIA: PURINETHOL is not effective for prophylaxis or
treatment of central nervous system leukemia.
OTHER NEOPLASMS: PURINETHOL is not effective in chronic lymphatic leukemia, the
lymphomas (including Hodgkin's Disease), or solid tumors.
CONTRAINDICATIONS:
PURINETHOL should not be used unless a diagnosis of acute lymphatic leukemia has
been adequately established and the responsible physician is knowledgeable in
assessing response to chemotherapy.
PURINETHOL 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.
WARNINGS:
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 KNOWLEDGEABLE IN ASSESSING RESPONSE TO
CHEMOTHERAPY.
SINCE DRUGS USED IN CANCER CHEMOTHERAPY ARE POTENTIALLY HAZARDOUS, IT IS
RECOMMENDED THAT ONLY PHYSICIANS EXPERIENCED WITH THE RISKS OF PURINETHOL AND
KNOWLEDGEABLE IN THE NATURAL HISTORY OF ACUTE LEUKEMIAS ADMINISTER THIS DRUG.
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 reflect progression of
the underlying disease. 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
mehyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive
effects of mercaptopurine and prone to developing rapid bone marrow depression
following the initiation of treatment. (REF. 6,7) Substantial dosage reductions
may be required to avoid the development of life-threatening bone marrow
depression in these patients. This toxicity may be more profound in patients
treated with concomitant allopurinol (see PRECAUTIONS: Drug Interactions).
HEPATOTOXICITY: mercaptopurine is hepatotoxic in animals and humans. A small
number of deaths have been reported which 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. (REF. 8)
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 any
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. (REF. 8) In reports of smaller cohorts of adult and
pediatric leukemic patients, the incidence of hepatotoxicity ranged from 0 to
6%. (REF. 9-11) In an isolated report by Einhorn and Davidsohn, jaundice was
observed more frequently (40%), especially when doses exceeded 2.5 mg/kg. (REF.
12) 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.
(REF. 13)
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. (REF. 14)
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 a search for an etiology of the
hepatotoxicity.
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 immunosuppressive effect should be carefully considered with regard to
intercurrent infections and risk of subsequent neoplasia.
PREGNANCY: Pregnancy Category D. Mercaptopurine can cause fetal harm when
administered to a pregnant woman. 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. (REF. 15) In a series of twenty-eight women receiving mercaptopurine
after the first trimester of pregnancy, three mothers died undelivered, one
delivered a stillborn child, and one aborted; there were no cases of
macroscopically abnormal fetuses. (REF. 16) 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.
There are no adequate and well-controlled studies in pregnant women. If this
drug is used during pregnancy or if the patient becomes pregnant while taking
the drug, the patient should be apprised of the potential hazard to the fetus.
Women of childbearing potential should be advised to avoid becoming pregnant.
PRECAUTIONS:
GENERAL: The safe and effective use of PURINETHOL demands a thorough knowledge
of the natural history of the condition being treated. 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 PURINETHOL 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 DELIBERATELY 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. 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.
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 metabolites and a greater cumulative effect.
INFORMATION FOR PATIENTS: Patients should be informed that the major toxicities
of PURINETHOL are related to myelosuppression, hepatotoxicity, and
gastrointestinal toxicity. Patients should never be allowed to take the drug
without medical supervision and should be advised to consult their physician if
they experience fever, sore throat, jaundice, nausea, vomiting, signs of local
infection, bleeding from any site, or symptoms suggestive of anemia. Women of
childbearing potential should be advised to avoid becoming pregnant.
LABORATORY TESTS: 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 therapy
with PURINETHOL. 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 PURINETHOL 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 in order to evaluate the effect of the therapy.
DRUG INTERACTIONS: INTERACTION WITH 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.
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. (REF. 17,18)
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: 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. (REF. 19) 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.
PREGNANCY: TERATOGENIC EFFECTS: Pregnancy Category D. See WARNINGS section.
NURSING MOTHERS: It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, and because of the potential for
serious adverse reactions in nursing infants from mercaptopurine, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
PEDIATRIC USE: See DOSAGE AND ADMINISTRATION section.
DRUG INTERACTIONS:
INTERACTION WITH 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.
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. (REF. 17,18)
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The principal and potentially serious toxic effects of PURINETHOL are bone
marrow toxicity and hepatotoxicity (see WARNINGS).
HEMATOLOGIC: The most frequent adverse reaction to PURINETHOL 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.
RENAL: Hyperuricemia may occur in patients receiving PURINETHOL 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 PURINETHOL should be reduced to one-third to one-quarter of the usual dose if
allopurinol is given concurrently.
GASTROINTESTINAL: Intestinal ulceration has been reported. (REF. 20) Nausea,
vomiting, and anorexia are uncommon during initial administration. 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 PURINETHOL in inflammatory bowel disease. (REF. 21-23)
MISCELLANEOUS: While dermatologic reactions can occur as a consequence of
disease, the administration of PURINETHOL has been associated with skin rashes
and hyperpigmentation. (REF. 24)
Drug fever has been very rarely reported with PURINETHOL. Before attributing
fever to PURINETHOL, every attempt should be made to exclude more common causes
of pyrexia, such as sepsis, in patients with acute leukemia.
OVERDOSAGE:
Signs and symptoms of overdosage may be immediate such as anorexia, nausea,
vomiting and diarrhea; or delayed such as 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 LD50 of mercaptopurine was determined to be 480 mg/kg in the mouse and
425 mg/kg in the rat. (REF. 25)
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.
DOSAGE AND ADMINISTRATION:
INDUCTION THERAPY: PURINETHOL is administered orally. The dosage which will be
tolerated and 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 pediatric
patients 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). Pediatric patients 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 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 lymphatic leukemia and high
total leukocyte counts.
The total daily dosage may be given at one time. It is calculated to the nearest
multiple of 25 mg. The dosage of PURINETHOL should be reduced to one-third to
one-quarter of the usual dose if allopurinol is given concurrently. Because 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: Once a complete hematologic remission is obtained,
maintenance therapy is considered essential. Maintenance doses will vary from
patient to patient. A usual daily maintenance dose of PURINETHOL 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 has been combined with other agents (most frequently with
methotrexate) for remission maintenance. PURINETHOL 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. (REF. 26-32)
There is no general agreement that all of the procedures recommended in the
guidelines are necessary or appropriate.
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