Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Hepatotoxicity
Additions and/or
revisions underlined:
Mercaptopurine is hepatotoxic. There are reports of deaths
attributed to hepatic necrosis associated with the administration of
mercaptopurine. Hepatic injury can occur with any dosage but seems to occur
with greater frequency when the recommended dosage is exceeded. In some
patients, jaundice has cleared following withdrawal of mercaptopurine and
reappeared with rechallenge.
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 starting
mercaptopurine. The hepatotoxicity has been associated in some cases with
anorexia, diarrhea, jaundice, ascites, and pruritus. Hepatic
encephalopathy has occurred.
Monitor serum transaminase levels, alkaline
phosphatase, and bilirubin levels at weekly intervals when first beginning
therapy and at monthly intervals thereafter. Monitor liver tests more
frequently in patients who are receiving PURINETHOL with other hepatotoxic
products [see Drug Interactions (7.5)] or
with known pre-existing liver disease. Withhold PURINETHOL at onset of
hepatotoxicity.
Intrahepatic Cholestasis of Pregnancy
Postmarketing cases of intrahepatic cholestasis of
pregnancy (ICP) have been reported in patients with inflammatory bowel disease
who received mercaptopurine during pregnancy. PURINETHOL is not indicated for
use in inflammatory bowel disease [see
Indications and Usage (1.1)].
Discontinue PURINETHOL if ICP develops in a pregnant
woman.
6
Adverse Reactions
6.2 Postmarketing
Experience
Newly added subsection:
The
following adverse reactions have been identified during postapproval use of
PURINETHOL. Because these reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure. These reactions
include: intrahepatic cholestasis of pregnancy (ICP).
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Myelosuppression
(subsection
revised, additions underlined)
The most consistent, dose-related adverse
reaction is myelosuppression, manifested by anemia, leukopenia,
thrombocytopenia, or any combination of these. Monitor CBC and adjust the
dosage of Mercaptopurine Tablets for excessive myelosuppression.
Consider testing for TPMT or NUDT15
deficiency in
patients with severe myelosuppression or repeated episodes of
myelosuppression. TPMT genotyping or phenotyping (red blood cell TPMT
activity) and NUDT15 genotyping can identify patients who have reduced activity
of these enzymes. Patients with heterozygous or homozygous TPMT or NUDT15 deficiency
may require a dose reduction .
Myelosuppression can be exacerbated by
coadministration with allopurinol, aminosalicylates or other products
that cause myelosuppression Reduce
the dose of Mercaptopurine Tablets when coadministered with allopurinol .
5.2 Hepatotoxicity
(subsection
revised, additions underlined)
Mercaptopurine is hepatotoxic. There
are reports of deaths attributed to hepatic necrosis associated with the
administration of mercaptopurine. Hepatic injury can occur with any dosage but
seems to occur with greater frequency when the recommended dosage is exceeded.
In some patients, jaundice has cleared following withdrawal of mercaptopurine
and reappeared with rechallenge.
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 starting
mercaptopurine. The hepatotoxicity has been associated in some cases with
anorexia, diarrhea, jaundice and ascites. Hepatic encephalopathy has occurred.
Monitor serum transaminase levels,
alkaline phosphatase, and bilirubin levels at weekly intervals when first
beginning therapy and at monthly intervals thereafter. Monitor liver tests more
frequently in patients who are receiving Mercaptopurine Tablets with other
hepatotoxic products or with known
pre-existing liver disease. Withhold Mercaptopurine Tablets at onset of
hepatotoxicity.
5.3 Immunosuppression
(subsection
revised, additions underlined)
Mercaptopurine is immunosuppressive and
may impair the immune response to infectious agents or vaccines. Due to the
immunosuppression associated with maintenance chemotherapy for ALL, response to
all vaccines may be diminished and there is a risk of infection with live virus
vaccines. Consult immunization guidelines for immunocompromised patients.
5.4 Treatment Related Malignancies
(new
subsection added)
Hepatosplenic T-cell lymphoma has been
reported in patients treated with mercaptopurine for inflammatory bowel disease
(IBD), an unapproved use. Mercaptopurine is mutagenic in animals and humans,
carcinogenic in animals, and may increase the risk of secondary malignancies.
Patients receiving immunosuppressive
therapy, including mercaptopurine, are at an increased risk of developing
lymphoproliferative disorders and other malignancies, notably skin cancers
(melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine
cervical cancer in situ. The increased risk appears to be related to the degree
and duration of immunosuppression. It has been reported that discontinuation of
immunosuppression may provide partial regression of the lymphoproliferative
disorder.
A
treatment regimen containing multiple immunosuppressants (including
thiopurines) should therefore be used with caution as this could lead to
lymphoproliferative disorders, some with reported fatalities. A combination of
multiple immunosuppressants,
given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated
lymphoproliferative disorders.
5.5 Macrophage Activation Syndrome
(new
subsection added)
Macrophage activation syndrome (MAS)
(hemophagocytic lymphohistiocytosis) is a known, life-threatening disorder that
may develop in patients with autoimmune conditions, in particular with
inflammatory bowel disease (IBD), and there could potentially be an increased
susceptibility for developing the condition with the use of mercaptopurine (an
unapproved use). If MAS occurs, or is suspected, discontinue Mercaptopurine
Tablets. Monitor for and promptly treat infections such as EBV and
cytomegalovirus (CMV), as these are known triggers for MAS.
5.6 Embryo-Fetal Toxicity
(subsection
revised, additions underlined)
Mercaptopurine Tablets can cause fetal
harm when administered to a pregnant woman. An increased incidence of miscarriage
has been reported in women who received mercaptopurine in the first trimester
of pregnancy. Adverse embryo-fetal findings, including miscarriage and
stillbirth, have been reported in women who received mercaptopurine after the
first trimester of pregnancy. Advise pregnant women of the potential risk to a
fetus. Advise females of reproductive potential to use effective contraception
during treatment with Mercaptopurine Tablets and for 6 months after the last
dose. Advise males with female partners of reproductive potential to use
effective contraception during treatment with Mercaptopurine Tablets and for 3
months after the last dose.
6
Adverse Reactions
(additions underlined)
The
following clinically significant adverse reactions are described elsewhere in
the labeling:
6.1 Clinical Trials Experience
(new subsection
added)
Because
clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to
rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
Based
on multicenter cooperative group ALL trials, the most common adverse reaction
occurring in > 20% of patients was myelosuppression, including anemia,
neutropenia, lymphopenia and thrombocytopenia.
Adverse reactions occurring in 5% to 20% of patients included anorexia,
nausea, vomiting, diarrhea, malaise and rash. Adverse reactions occurring in
< 5 % of patients included urticaria, hyperuricemia, oral lesions, increased
transaminases, hyperbilirubinemia, hyperpigmentation, infections, and
pancreatitis. Oral lesions resemble thrush rather than antifolic ulcerations.
Delayed or late adverse reactions include hepatic fibrosis, hyperbilirubinemia,
alopecia, pulmonary fibrosis, oligospermia and secondary malignancies.
Drug
fever has been reported with mercaptopurine.
Additional
adverse reactions that have been reported in patients who have received
mercaptopurine include photosensitivity, hypoglycemia, and portal hypertension.
7
Drug Interactions
(the following new
subsections created, please refer to label for complete information)
7.1 Allopurinol
7.2 Warfarin
7.3 Myelosuppressive Products
7.4 Aminosalicylates
7.5 Hepatotoxic Products
8
Use in Specific Populations
8.1 Pregnancy
(PLLR conversion)
Risk
Summary
Mercaptopurine
Tablets can cause fetal harm when administered to a pregnant woman. Pregnant
women who receive mercaptopurine have an increased incidence of miscarriage and
stillbirth (see Data). Advise
pregnant women of the potential risk to a fetus.
The
estimated background risk of major birth defects and miscarriage for the
indicated population(s) is unknown. All pregnancies have a background risk of
birth defect, loss, or other adverse outcomes. In the U.S. general population,
the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Human Data
Women
receiving mercaptopurine in the first trimester of pregnancy have an increased
incidence of miscarriage; the risk of malformation in offspring surviving first
trimester exposure is not known. In a series of 28 women receiving mercaptopurine
after the first trimester of pregnancy, 3 mothers died prior to delivery, 1
delivered a stillborn child, and 1 aborted; there were no cases of
macroscopically abnormal fetuses.
Animal Data
Mercaptopurine
was embryo-lethal and teratogenic in several animal species (rat, mouse,
rabbit, and hamster) at doses less than the recommended human dose.
8.2 Lactation
(PLLR conversion)
Risk
Summary
There
are no data on the presence of mercaptopurine or its metabolites in human milk,
the effects on the breastfed child, or the effects on milk production. Because
of the potential for serious adverse reactions in the breastfed child, advise
women not to breastfeed during treatment with Mercaptopurine Tablets and for 1
week after the last dose.
8.3 Females and Males of Reproductive Potential
(PLLR conversion)
Mercaptopurine
Tablets can cause fetal harm when administered to pregnant women.
Pregnancy
Testing
Verify
the pregnancy status in females of reproductive potential prior to initiating
Mercaptopurine Tablets.
Contraception
Females
Advise
females of reproductive potential to use effective contraception during treatment
with Mercaptopurine Tablets and for 6 months after the last dose.
Males
Based
on genotoxicity findings, advise males
with female partners of reproductive
potential to use effective contraception during treatment with
Mercaptopurine Tablets and for 3 months after the last dose.
Infertility
Females
and Males
Based
on findings from animal studies, Mercaptopurine Tablets can impair female and
male fertility.The long-term effects of mercaptopurine on female and male
fertility, including the reversibility have not been studied.
8.4 Pediatric Use
(new
subsection added)
Safety
and effectiveness of Mercaptopurine Tablets has been established in pediatric
patients. Use of Mercaptopurine Tablets in pediatrics is supported by evidence
from the published literature and clinical experience. Symptomatic hypoglycemia
has been reported in pediatric patients with ALL receiving mercaptopurine.
Reported cases were in pediatrics less than 6 years of age or with a low body
mass index.
8.6 Renal Impairment
(subsection
revised, additions underlined)
Use
the lowest recommended starting dosage for Mercaptopurine Tablets or increase
the dosing interval to every 36- 48 hours in patients with renal impairment
(CLcr less than 50 mL/min). Adjust the dose to maintain absolute neutrophil
count (ANC) at a desirable level and for adverse reactions.
8.7 Hepatic Impairment
(additions
underlined)
Use
the lowest recommended starting dosage for Mercaptopurine Tablets in patients
with hepatic impairment. Adjust the dose to maintain absolute neutrophil count
(ANC) at a desirable level and for adverse reactions.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(new subsection
created, please refer to label for complete information)
Other
Approved Drug Label (PDF)
4
Contraindications
(Additions and/or revisions are underlined)
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.
Mercaptopurine should not be
used in patients who have a hypersensitivity to mercaptopurine or any component
of the formulation.
5
Warnings and Precautions
WARNINGS
(Additions and/or revisions are underlined)
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. In many patients with severe depression of the formed
elements of the blood due to mercaptopurine…
Evaluate patients with repeated severe
myelosuppression for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase
(NUDT15) deficiency. TPMT genotyping or phenotyping (red blood cell TPMT activity)
and NUDT15 genotyping can identify patients who have reduced activity of these enzymes.
Patients with homozygous TPMT or NUDT15 deficiency require substantial dosage reductions.
PRECAUTIONS
(Additions and/or revisions are underlined)
General
The safe and effective use of mercaptopurine
…
Information for Patients
Patients should be informed that the
major toxicities of mercaptopurine...
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 mercaptopurine. Bone marrow examination may also be useful for the evaluation
of marrow status. The decision to increase, decrease, continue, or discontinue a
given dosage of mercaptopurine must be based upon the degree of severity
and 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. Consider
testing for TPMT and NUDT15 deficiency in patients who experience severe bone
marrow toxicities or repeated episodes of myelosuppression.
Geriatric Use
Clinical studies of mercaptopurine…
6
Adverse Reactions
(Additions and/or revisions are underlined)
The principal and potentially serious toxic effects of
mercaptopurine are bone marrow toxicity and hepatotoxicity.
Hematologic
The most frequent adverse reaction to
mercaptopurine is myelosuppression…
Renal
Hyperuricemia and/or hyperuricosuria
may occur in patients receiving mercaptopurine as a consequence of rapid
cell lysis accompanying the antineoplastic effect. Renal 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
The administration of mercaptopurine
has been associated with skin rashes and hyperpigmentation. Alopecia has been reported.
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.
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