Mercaptopurine

Mercaptopurine is a nucleoside metabolic inhibitor indicated for the treatment of patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen. ( 1.1 )

1.1 Acute Lymphoblastic Leukemia Mercaptopurine is indicated for the treatment of patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen.

• The recommended starting dosage of mercaptopurine oral suspension is 1.5 mg/kg to 2.5 mg/kg (50 mg/m 2 to 75 mg/m 2 ) 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 dose of mercaptopurine oral suspension is 1.5 mg/kg to 2.5 mg/kg (50 mg/m 2 to 75 mg/m 2 ) orally once daily as part of combination chemotherapy maintenance regimen. Take mercaptopurine oral suspension either consistently with or without food [see Clinical Pharmacology ( 12.3 )] . After initiating mercaptopurine, monitor complete blood counts (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 of myelosuppression [see Dosage and Administration ( 2.2 )] . If a patient misses a dose, instruct the patient to continue with the next scheduled dose.

2.2 Dosage Modifications in Patients with TPMT and/or 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 in patients who are known to have homozygous TPMT or NUDT15 deficiency. Heterozygous Deficiency in TPMT and/or NUDT15 Reduce the mercaptopurine dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended dosage, but some require 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 or increase the dosing interval to every 36 to 48 hours 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 in patients with hepatic impairment. Adjust the dosage to maintain absolute neutrophil count (ANC) at a desirable level and for adverse reactions [see Use in Specific Populations ( 8.7 )] .

2.4 Dosage Modification with Concomitant Use of Allopurinol Reduce the dose of mercaptopurine to one-third to one-quarter of the current dosage when coadministered with allopurinol [see Drug Interactions ( 7.1 )] .

2.5 Administration Shake the bottle vigorously for at least 30 seconds to ensure the oral suspension is well mixed. Mercaptopurine oral suspension is a pink to brown viscous oral suspension. Provide a press-in bottle adapter and two oral dispensing syringes (one 1 mL and one 5 mL). Train patients or caregivers on proper handling, storage, administration, disposal and clean-up of accidental spillage prior to initiation of mercaptopurine oral suspension and during each visit to the clinic. Advise patients and caregivers to use mercaptopurine oral suspension within 8 weeks and properly discard remaining mercaptopurine oral suspension after 8 weeks. Provide instructions regarding which syringe to use and how to administer the specified dose, since mercaptopurine oral suspension is supplied with 1 mL and 5 mL oral dispensing syringes. Advise patients that the oral dispensing syringe is intended for multiple uses and provide the following instructions:

• Wash the oral dispensing syringe with warm ‘soapy’ water and rinse well;
• Hold the oral dispensing syringe under water and move the plunger up and down several times to make sure the inside of the oral dispensing syringe is clean;
• Ensure the oral dispensing syringe is completely dry before use of the oral dispensing syringe again; and
• Store the oral dispensing syringe in a hygienic place with mercaptopurine oral suspension. Mercaptopurine is a hazardous drug. Follow special handling and disposal procedures. 1

Oral Suspension: 2,000 mg/100 mL (20 mg/mL) pink to brown in color. Oral suspension: 2,000 mg/100 mL (20 mg/mL) ( 3 )

None.

• None

• Allopurinol : Reduce the dose of mercaptopurine when coadministered with allopurinol. ( 2.4 , 7.1 )
• Warfarin : Mercaptopurine may decrease the anticoagulant effect. Monitor INR and adjust warfarin dose as appropriate. ( 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 [see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 )] . Reduce the dose of mercaptopurine when coadministered with allopurinol [see Dosage and Administration ( 2.4 )] .

7.2 Warfarin The coadministration of mercaptopurine with 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 can cause myelosuppression. Myelosuppression may be increased when mercaptopurine is coadministered with other drugs that cause myelosuppression. Enhanced myelosuppression has been noted in some patients receiving trimethoprim-sulfamethoxazole. Monitor the CBC and adjust the dose of mercaptopurine 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. When aminosalicylates and mercaptopurine 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 can cause hepatotoxicity. Hepatotoxicity may be increased when mercaptopurine is coadministered with other products that cause hepatotoxicity. Monitor liver tests more frequently in patients who are receiving mercaptopurine with other hepatotoxic products [see Warnings and Precautions ( 5.2 )] .

7.6 Methotrexate Mercaptopurine dosage may need adjustment when administered concomitantly with high dose methotrexate [see Warnings and Precautions ( 5.1 )] . Mercaptopurine exposure increases with concomitant methotrexate use [see Clinical Pharmacology ( 12.3 )] which may increase the risk of mercaptopurine adverse reactions. The mechanism of this interaction has not been fully characterized [see Clinical Pharmacology ( 12.3 )] .

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, neutropenia, lymphopenia 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, elevated transaminases, hyperbilirubinemia, hyperpigmentation, infections, and pancreatitis. Oral lesions resemble thrush rather than antifolic ulcerations. Delayed or late toxicities 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.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of mercaptopurine. 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: photosensitivity, hypoglycemia, portal hypertension, intrahepatic cholestasis of pregnancy (ICP), pellagra, erythema nodosum, and mucosal inflammation.

Signs and symptoms of mercaptopurine overdosage may be immediate (anorexia, nausea, vomiting, and diarrhea) or delayed (myelosuppression, liver dysfunction, gastroenteritis, and mucosal inflammation). 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 immediately if 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.

• Lactation : Advise not to breastfeed. ( 8.2 )
• Infertility : Can impair fertility. ( 8.3 )

8.1 Pregnancy Risk Summary Mercaptopurine 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 and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential Mercaptopurine 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 [see Use in Specific Populations ( 8.1 )] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment with mercaptopurine 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 and for 3 months after the last dose [see Nonclinical Toxicology ( 13.1 )] . Infertility Females and Males Based on findings from animal studies, mercaptopurine 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 have been established in pediatric patients. Use of mercaptopurine 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 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 or increase the dosing interval to every 36 to 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 [see Dosage and Administration ( 2.3 )] .

8.7 Hepatic Impairment Use the lowest recommended starting dosage for mercaptopurine in patients with hepatic impairment. Adjust the dose to maintain absolute neutrophil count (ANC) at a desirable level and for adverse reactions [see Dosage and Administration ( 2.3 )] .

Risk Summary Mercaptopurine 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.

Safety and effectiveness of mercaptopurine have been established in pediatric patients. Use of mercaptopurine 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 or with a low body mass index.

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.

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. The structural formula is: Mercaptopurine, USP is a yellow, crystalline powder; odorless. It is practically insoluble in water and in ether; slightly soluble in ethanol (96%). It dissolves in solutions of alkali hydroxides; pKa 7.8, 11.2. Mercaptopurine oral suspension contains 2,000 mg/100 mL (20 mg/mL) of mercaptopurine, USP. The suspension also contains the following inactive ingredients: aspartame, ethylparaben sodium, hydrochloric acid, methylparaben sodium, potassium sorbate, raspberry juice powder (raspberry juice, rice syrup solids, silicon dioxide), sodium hydroxide, sucrose, water (purified), xanthan gum. Mercaptopurine oral suspension is a pink to brown viscous suspension. Chemical Structure

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.

Exposure-Response Relationships Mercaptopurine exposure-response relationships and the time course of pharmacodynamics response are unknown.

Following a single oral dose of mercaptopurine 50 mg under fasted conditions to adult healthy subjects, the median (min – max) AUC 0-INF was 137 h∙ng/mL (77 – 268 h∙ng/mL) and C max was 93 ng/mL (40 – 204 ng/mL). Absorption Mercaptopurine is absorbed after oral administration with a median (min – max) T max of 0.75 (0.33 – 2.5) hours. Effect of Food Food has been shown to decrease the exposure of mercaptopurine. Distribution The volume of distribution exceeds total body water with a mean volume of distribution of approximately 0.9 L/kg. There is negligible entry of mercaptopurine into cerebrospinal fluid. Plasma protein binding averages 19% over the concentration range 10 to 50 mcg/L. Elimination The median (min – max) elimination half-life (t 1/2 ) was 1.3 (0.9 – 5.4) hours. Metabolism Mercaptopurine is inactivated via two major pathways. One is thiol methylation, which is catalyzed by the polymorphic enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-mercaptopurine. The second inactivation pathway is oxidation, which is catalyzed by xanthine oxidase. The product of oxidation is the inactive metabolite 6-thiouric acid. Elimination After oral administration of mercaptopurine, urine contains intact mercaptopurine, thiouric acid (formed by direct oxidation by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine), and a number of 6-methylated thiopurines. In one subject, a total of 46% of the dose could be accounted for in the urine (as parent drug and metabolites) in the first 24 hours. Specific Populations Pediatric Patients Wide inter individual variations in systemic exposure is observed. Following oral administration of 50 mg/m 2 mercaptopurine in 10 children, median plasma concentrations 1 hour post dose was 0.35 (range 0.03 to 1.03) μM and median AUC 1–5hours was 56 (range 23 to 65) μM·min. T max ranged from 1 to 3 hours. Drug Interactions Studies Methotrexate: Mercaptopurine AUC increased by approximately 31% when coadministered with oral methotrexate 20 mg/m 2 . Mercaptopurine AUC increased by 69% when coadministered with IV methotrexate 2 g/m 2 , and by 93% when coadministered with IV methotrexate 5 g/m 2 .

, Mutagenesis, Impairment of Fertility Mercaptopurine is carcinogenic in animals. Mercaptopurine causes chromosomal aberrations in cells derived from animals and humans and induces dominant-lethal mutations in the germ cells of male mice. Mercaptopurine can impair fertility. In mice, surviving female offspring of mothers who received chronic low doses of mercaptopurine during pregnancy were found sterile, or if they became pregnant, had smaller litters and more dead fetuses as compared to control animals.

17 PATIENT COUNSELING INFORMATION Advise the patients and caregivers to read the FDA-approved patient labelling (Patient Information and Instructions for Use). Major Adverse Reactions Advise patients and caregivers that mercaptopurine 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 )] . Proper Preparation and Administration Advise patients or caregivers on proper handling, storage, preparation, administration, and disposal and clean-up of accidental spillage of the medication prior to initiation and on each visit to the clinic [see Dosage and Administration ( 2.5 )] . 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 ( 5.2 , 5.6 ), Use in Specific Populations ( 8.1 )] .
• Advise females of reproductive potential to use effective contraception during treatment with mercaptopurine 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 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 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 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 ( 6.2 )] . Patients with Phenylketonuria Inform patients with phenylketonuria that each mL of mercaptopurine oral suspension contains 0.015 mg of phenylalanine [see Warnings and Precautions ( 5.7 )] . Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 C50001544/02 Revised July 2026