mercaptopurine 50 MG Oral Tablet
Generic Name: MERCAPTOPURINE
Brand Name: Mercaptopurine
- Substance Name(s):
- MERCAPTOPURINE
DRUG INTERACTIONS
7 • Allopurinol : Reduce the dose of mercaptopurine tablets when co-administered with allopurinol.
( 2.4 , 7.1 ) • Warfarin : Mercaptopurine tablets may decrease the anticoagulant effect.
( 7.2 ) 7.1 Allopurinol Allopurinol can inhibit the first-pass oxidative metabolism of mercaptopurine by xanthine oxidase, which can lead to an increased risk of mercaptopurine adverse reactions (i.e., myelosuppression, nausea, and vomiting) [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ] .
Reduce the dose of mercaptopurine tablets when coadministered with allopurinol [see Dosage and Administration (2.4) ] .
7.2 Warfarin The concomitant administration of mercaptopurine tablets and warfarin may decrease the anticoagulant effectiveness of warfarin.
Monitor the international normalized ratio (INR) in patients receiving warfarin and adjust the warfarin dosage as appropriate.
7.3 Myelosuppressive Products Mercaptopurine tablets can cause myelosuppression.
Myelosuppression may be increased when mercaptopurine tablets are coadministered with other products that cause myelosuppression.
Enhanced myelosuppression has been noted in some patients also receiving trimethoprim-sulfamethoxazole.
Monitor the CBC and adjust the dose of mercaptopurine tablets for excessive myelosuppression [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ] .
7.4 Aminosalicylates Aminosalicylates (e.g., mesalamine, olsalazine or sulfasalazine) may inhibit the TPMT enzyme, which may increase the risk of myelosuppression when coadministered with mercaptopurine tablets.
When aminosalicylates and mercaptopurine tablets are coadministered, use the lowest possible doses for each drug and monitor more frequently for myelosuppression [see Warnings and Precautions (5.1) ] .
7.5 Hepatotoxic Products Mercaptopurine tablets can cause hepatotoxicity.
Hepatotoxicity may be increased when mercaptopurine tablets are coadministered with other products that cause hepatotoxicity.
Monitor liver tests more frequently in patients who are receiving mercaptopurine tablets with other hepatotoxic products [see Warnings and Precautions (5.2) ] .
OVERDOSAGE
10 Signs and symptoms of mercaptopurine overdosage may be immediate (anorexia, nausea, vomiting, and diarrhea); or delayed (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.
Withhold mercaptopurine tablets immediately for severe or life-threatening adverse reactions occur during treatment.
If a patient is seen immediately following an accidental overdosage, it may be useful to induce emesis.
DESCRIPTION
11 Mercaptopurine is a nucleoside metabolic inhibitor, the chemical name is Purine-6-thiol monohydrate.
The molecular formula is C 5 H 4 N 4 S•H 2 O and the molecular weight is 170.20.
Its structural formula is: Mercaptopurine, USP is a yellow, crystalline powder.
Mercaptopurine is practically insoluble in water and in ether.
It has a pKa of 7.8, an average tapped density of 1.0 g/mL and average bulk density of 0.85 g/mL.
It dissolves in solutions of alkali hydroxides.
Mercaptopurine tablets are available for oral use.
Each scored tablet contains 50 mg mercaptopurine and the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, pregelatinized starch (corn) and sodium lauryl sulfate.
Meets USP Dissolution Test 2.
Mercaptopurine Structural Formula
HOW SUPPLIED
16 /STORAGE AND HANDLING Mercaptopurine Tablets, USP are available containing 50 mg of mercaptopurine, USP.
The 50 mg tablets are off-white to light yellow, round, scored tablets debossed with M above the score and 547 below the score on one side of the tablet and blank on the other side.
They are available as follows: NDC 0378-3547-52 bottles of 25 tablets NDC 0378-3547-25 bottles of 250 tablets Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature.] Protect from moisture.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Mercaptopurine tablets are a cytotoxic drug.
Follow special handling and disposal procedures.
1
GERIATRIC USE
8.5 Geriatric Use Clinical studies of mercaptopurine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or another drug therapy.
DOSAGE FORMS AND STRENGTHS
3 Mercaptopurine Tablets, USP are available containing 50 mg of mercaptopurine, USP.
• The 50 mg tablets are off-white to light yellow, round, scored tablets debossed with M above the score and 547 below the score on one side of the tablet and blank on the other side.
Tablets: 50 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Mercaptopurine is a purine analog that undergoes intracellular transport and activation to form metabolites including thioguanine nucleotides (TGNs).
Incorporation of TGNs into DNA or RNA results in cell-cycle arrest and cell death.
TGNs and other mercaptopurine metabolites are also inhibitors of de novo purine synthesis and purine nucleotide interconversions.
Mercaptopurine was cytotoxic to proliferating cancer cells in vitro and had antitumor activity in mouse tumor models.
It is not known which of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death.
INDICATIONS AND USAGE
1 Mercaptopurine tablets are a nucleoside metabolic inhibitor indicated for treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen.
( 1.1 ) 1.1 Acute Lymphoblastic Leukemia Mercaptopurine tablets are indicated for treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen.
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness of mercaptopurine tablets have 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.
PREGNANCY
8.1 Pregnancy Risk Summary Mercaptopurine tablets can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] .
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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Myelosuppression : Monitor complete blood count (CBC) and adjust the dose of mercaptopurine tablets for excessive myelosuppression.
Consider testing in patients with severe myelosuppression or repeated episodes of myelosuppression for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency.
Patients with homozygous or homozygous TPMT or NUDT15 deficiency may require a dose reduction.
( 2.2 , 5.1 ) • Hepatotoxicity : Monitor transaminases, alkaline phosphatase and bilirubin.
Withhold mercaptopurine tablets at onset of hepatotoxicity.
( 5.2 ) • Immunosuppression : Response to all vaccines may be diminished and there is a risk of infection with live virus vaccines.
Consult immunization guidelines for immunocompromised patients.
( 5.3 ) • Treatment Related Malignancies : Aggressive and fatal cases of hepatosplenic T-cell lymphoma have occurred.
( 5.4 ) • Macrophage Activation Syndrome : Monitor for and treat promptly; discontinue mercaptopurine tablets.
( 5.5 ) • Embryo-Fetal Toxicity : Can cause fetal harm.
Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception.
( 5.6 , 8.1 , 8.3 ) 5.1 Myelosuppression 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 [see Dosage and Administration (2.1) ] .
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 [see Dosage and Administration (2.2), Clinical Pharmacology (12.5) ] .
Myelosuppression can be exacerbated by coadministration with allopurinol, aminosalicylates or other products that cause myelosuppression [see Drug Interactions (7.1 , 7.3 , 7.4) ] .
Reduce the dose of mercaptopurine tablets when coadministered with allopurinol [see Dosage and Administration (2.4) ] .
5.2 Hepatoxicity 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 [see Drug Interactions (7.5) ] or with known pre-existing liver disease.
Withhold mercaptopurine tablets at onset of hepatotoxicity.
5.3 Immunosuppression 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 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 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 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 [see Use in Specific Populations (8.1 , 8.3) ] .
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Major Adverse Reactions: Advise patients and caregivers that mercaptopurine tablets can cause myelosuppression, hepatotoxicity, and gastrointestinal toxicity.
Advise patients to contact their healthcare provider if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] .
Embryo-Fetal Toxicity: • Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6) , Use in Specific Populations (8.1) ] .
• Advise females of reproductive potential to use effective contraception during treatment with mercaptopurine tablets and for 6 months after the last dose [see Use in Specific Populations (8.3) ] .
• 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 [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ] .
Lactation: Advise women not to breastfeed during treatment with mercaptopurine tablets and for 1 week after the last dose [see Use in Specific Populations (8.2) ] .
Infertility: Advise males and females of reproductive potential that mercaptopurine tablets can impair fertility [see Use in Specific Populations (8.3) ] .
Other Adverse Reactions: Instruct patients to minimize sun exposure due to risk of photosensitivity [see Adverse Reactions (6.1) ] .
Manufactured for: Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
Manufactured by: Auro PR Inc.
RD 156 Caguas West Industrial Park, Lot 24 Caguas, PR 00725 U.S.A.
Revised: 3/2022 MCPT:R8
DOSAGE AND ADMINISTRATION
2 • The recommended starting dose of mercaptopurine tablets is 1.5 mg/kg to 2.5 mg/kg orally once daily as part of a combination chemotherapy maintenance regimen.
Adjust dose to maintain desirable absolute neutrophil count and for excessive myelosuppression.
( 2.1 ) • Renal Impairment : Use the lowest recommended starting dose or increase the dosing interval.
( 2.3 , 8.6 ) • Hepatic Impairment : Use the lowest recommended starting dose.
( 2.3 , 8.7 ) 2.1 Recommended Dosage The recommended starting dosage of mercaptopurine tablets is 1.5 mg/kg to 2.5 mg/kg orally once daily as part of combination chemotherapy maintenance regimen.
A recommended dosage for patients less than 17 kg is not achievable, because the only available strength is 50 mg.
Take mercaptopurine tablets either consistently with or without food.
After initiating mercaptopurine tablets, monitor complete blood count (CBC) and adjust the dose to maintain absolute neutrophil count (ANC) at a desirable level and for excessive myelosuppression.
Evaluate the bone marrow in patients with prolonged myelosuppression or repeated episodes of myelosuppression to assess leukemia status and marrow cellularity.
Evaluate thiopurine S-methyltransferase (TPMT) and nucleotide diphosphatase (NUDT15) status in patients with severe myelosuppression or repeated episodes or myelosuppression [see Dosage and Administration (2.2) ] .
Do not administer to patients who are unable to swallow tablets.
If a patient misses a dose, instruct the patient to continue with the next scheduled dose.
Mercaptopurine tablets are a cytotoxic drug.
Follow special handling and disposal procedures.
1 2.2 Dosage Modifications in Patients with TPMT and NUDT15 Deficiency Consider testing for TPMT and NUDT15 deficiency in patients who experience severe myelosuppression or repeated episodes of myelosuppression [see Warnings and Precautions (5.1) , Clinical Pharmacology (12.5) ] .
Homozygous Deficiency in either TPMT or NUDT15 Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage.
Reduce the recommended starting dosage of mercaptopurine tablets in patients who are known to have homozygous TPMT or NUDT15 deficiency.
Heterozygous Deficiency in TPMT and/or NUDT15 Reduce the mercaptopurine tablets dose based on tolerability.
Most patients with heterozygous TPMT or NUDT15 deficiency tolerate the recommended dosage, but some require a dose reduction based on adverse reactions.
Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.
2.3 Dosage Modifications in Renal and Hepatic Impairment Renal Impairment Use the lowest recommended starting dosage for mercaptopurine tablets in patients with renal impairment (CLcr less than 50 mL/min).
Adjust the dosage to maintain absolute neutrophil count (ANC) at a desirable level and for adverse reactions [see Uses in Specific Populations (8.6) ] .
Hepatic Impairment Use the lowest recommended starting dosage for mercaptopurine tablets in patients with hepatic impairment.
Adjust the dosage to maintain absolute neutrophil count (ANC) at a desirable level and for adverse reactions [see Uses in Specific Populations (8.7) ] .
2.4 Dosage Modification with Concomitant Use of Allopurinol Reduce the dose of mercaptopurine tablets to one-third to one-quarter of the current dosage when coadministered with allopurinol [see Drug Interactions (7.1) ] .