Mercaptopurine

1 INDICATIONS AND USAGE Mercaptopurine Tablets is 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.

2 DOSAGE AND 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 is 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 Use 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 )].

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 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 )]. DiscontinueMercaptopurine 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 chemoth…

4 CONTRAINDICATIONS None. None.

7 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 )].

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 .

12.5 Pharmacogenomics Several published studies indicate that patients with reduced TPMT or NUDT15 activity receiving usual doses of mercaptopurine, accumulate excessive cellular concentrations of active 6-TGNs, and are at higher risk for severe myelosuppression. In a study of 1028 children with ALL, the approximate tolerated mercaptopurine dosage for patients with TPMT and/or NUDT15 deficiency on mercaptopurine maintenance therapy (as a percentage of the planned dosage) was as follows: heterozygous for either TPMT or NUDT15, 50 to 90%; heterozygous for both TPMT and NUDT15, 30 to 50%; homozygous for either TPMT or NUDT15, 5 to 10%. Approximately 0.3% (1:300) of patients of European or African ancestry have two loss-of-function alleles of the TPMT gene and have little or no TPMT activity (homozygous deficient or poor metabolizers), and approximately 10% of patients have one loss-of-function TPMT allele leading to intermediate TPMT activity (heterozygous deficient or intermediate metabolizers). The TPMT*2, TPMT*3A, and TPMT*3C alleles account for about 95% of individuals with reduced levels of TPMT activity. NUDT15 deficiency is detected in <1% of patients of European or African ancestry. Among patients of East Asian ancestry (i.e., Chinese, Japanese, Vietnamese), 2% have two loss-of-function alleles of the NUDT15 gene, and approximately 21% have one loss-of-function allele. The p.R139C variant of NUDT15 (present on the *2 and *3 alleles) is the most commonly observed, but other less common loss-of-function NUDT15 alleles have been observed. Consider all clinical information when interpreting results from phenotypic testing used to determine the level of thiopurine nucleotides or TPMT activity in erythrocytes, since some coadministered drugs can influence measurement of TPMT activity in blood and blood from recent transfusions will misrepresent a patient’s actual TPMT activity [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 )].

6 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 Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 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).