Mercaptopurine

Warnings and Precautions, Hepatotoxicity (5.2) 07/2024

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 )].

3 DOSAGE FORMS AND STRENGTHS Tablets: 50 mg mercaptopurine are pale yellow, biconvex tablets, with product identification “54 420” on one side and a score on the other side. Tablets: 50 mg (3)

4 CONTRAINDICATIONS None. None.

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).

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 USE IN SPECIFIC POPULATIONS • Lactation: Advise not to breastfeed. (8.2) • Infertility: Can impair fertility. (8.3) 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 . 8.2 Lactation 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 Mercaptopurine Tablets can cause fetal harm when administered to pregnant women [see Use in Specific Populations ( 8.1 )]. Pregnancy Testing Verify the pregnancy status in females of reproductive potential prior to initiating Mercaptopurine Tablets [see Use in Specific Populations (8.1 )]. 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 [see Nonclinical Toxicology ( 13.1 )]. Infertility Females and Males Based on findings from animal studies, Mercaptopurine Tablets can impair female and male fertility [see Nonclinical Toxicology ( 13.1 )]. The long-term effects of mercaptopurine on female and male fertility, including the reversibility have not been studied. 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. 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. 8.6 Renal Impairment Use the lowest recommended starting dosage for Mercaptopurine Tablets or increase the dosing interval to every 36 to 48 hours in pat …

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.

11 DESCRIPTION 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 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, USP are available for oral use. Each scored tablet contains 50 mg mercaptopurine, USP and the following inactive ingredients: corn starch, hypromellose, lactose (anhydrous), lactose monohydrate, magnesium stearate, potato starch, sodium starch glycolate and stearic acid. Each tablet meets the requirements of Test 2 for Dissolution in the USP monograph for Mercaptopurine Tablets, USP. image-01.jpg

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Mercaptopurine tablets are supplied as biconvex, round, pale yellow to buff, scored tablets containing 50 mg mercaptopurine, imprinted with “9|3” available in: bottles of 25 NDC 71921-150-02 bottles of 250 NDC 71921-150-25 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in a dry place. Dispense in tight container as defined in the USP. Mercaptopurine tablets is a cytotoxic drug. Follow special handling and disposal procedures.