Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/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.; PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0378-3547-52 Mercaptopurine Tablets, USP 50 mg Cytotoxic Agent Rx only 25 Tablets Each tablet contains: Mercaptopurine, USP 50 mg Usual Dosage: See accompanying prescribing information. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Keep container tightly closed. Keep this and all medication out of the reach of children. Store at 20° to 25°C (68° to 77°F ). [See USP Controlled Room Temperature.] Protect from moisture. WARNING: This drug is only to be taken under close medical supervision. Do not take in larger doses or more frequently or for a longer time than specifically directed by the physician. Periodic blood counts are necessary to determine proper dose and to avoid ill effects. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in Puerto Rico RM3547BA6 Mercaptopurine Tablets, USP 50 mg Bottle Label
- 16 HOW SUPPLIED/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.
- PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0378-3547-52 Mercaptopurine Tablets, USP 50 mg Cytotoxic Agent Rx only 25 Tablets Each tablet contains: Mercaptopurine, USP 50 mg Usual Dosage: See accompanying prescribing information. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Keep container tightly closed. Keep this and all medication out of the reach of children. Store at 20° to 25°C (68° to 77°F ). [See USP Controlled Room Temperature.] Protect from moisture. WARNING: This drug is only to be taken under close medical supervision. Do not take in larger doses or more frequently or for a longer time than specifically directed by the physician. Periodic blood counts are necessary to determine proper dose and to avoid ill effects. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in Puerto Rico RM3547BA6 Mercaptopurine Tablets, USP 50 mg Bottle Label
Overview
Mercaptopurine is a nucleoside metabolic inhibitor, the chemical name is 6 H -purine-6-thione, 1,7-dihydro-,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
Indications & Usage
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.
Dosage & Administration
• 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. 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) ] .
Warnings & 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 Hepatotoxicity 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 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. 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. Mercaptopurine tablets are not indicated for use in inflammatory bowel disease [see Indications and Usage (1.1) ] . Discontinue mercaptopurine tablets if ICP develops in a pregnant woman. 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) ] .
Contraindications
None. None.
Adverse Reactions
The following clinically significant adverse reactions are described elsewhere in the labeling: • Myelosuppression [see Warnings and Precautions (5.1) ] • Hepatotoxicity [see Warnings and Precautions (5.2) ] • Immunosuppression [see Warnings and Precautions (5.3) ] • Treatment related malignancies [see Warnings and Precautions (5.4) ] • Macrophage activation syndrome [see Warnings and Precautions (5.5) ] The most common adverse reaction (> 20%) is myelosuppression, including anemia, leukopenia and thrombocytopenia. Adverse reactions occurring in 5% to 20% of patients include anorexia, nausea, vomiting, diarrhea, malaise and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 [see Warnings and Precautions (5.1 , 5.2) ] . 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of mercaptopurine tablets. 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).
Drug Interactions
• 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) ] .
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