Mercaptopurine

Q: What should I know before taking Mercaptopurine?

5 WARNINGS AND PRECAUTIONS • Myelosuppression : Monitor complete blood count (CBC) and adjust the dose of mercaptopurine 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-TPMT or homozygous-NUDT15 deficiency may require a dose reduction. ( 2.2 , 5.1 ) • Hepatotoxicity : Monitor transaminases, alkaline

Q: Is Mercaptopurine available over the counter?

Mercaptopurine is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Prescription

Handelsnamen: MERCAPTOPURINE

Darreichungsform

Liquid/Solution

Applikationsweg

ORAL

Hersteller

Hikma Pharmaceuticals USA Inc.

About This Medication

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. 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

Wirkstoffe

Wirkstoff	Stärke
Mercaptopurine	-

Indikationen und Anwendung

1 INDICATIONS AND USAGE 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.

So funktioniert es

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.

Dosierung und Verabreichung

2 DOSAGE AND ADMINISTRATION • 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. 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 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 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 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 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

Side Effects Overview

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, 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, and erythema nodosum.

Warnhinweise und Vorsichtsmaßnahmen

5 WARNINGS AND PRECAUTIONS • Myelosuppression : Monitor complete blood count (CBC) and adjust the dose of mercaptopurine 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-TPMT or homozygous-NUDT15 deficiency may require a dose reduction. ( 2.2 , 5.1 ) • Hepatotoxicity : Monitor transaminases, alkaline phosphatase and bilirubin. Withhold mercaptopurine 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 pediatrics. ( 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. ( 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 ) • Phenylketonuria : Patients should be informed that mercaptopurine oral suspension contains phenylalanine, a component of aspartame. Each mL of the 20 mg/mL oral suspension contains 0.015 mg of phenylalanine. ( 5.7 ) 5.1 Myelosuppression The most consistent, dose-related adverse reaction of mercaptopurine is myelosuppression, manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. Monitor CBC and adjust the dosage of mercaptopurine for excessive myelosuppression [see Dosage and Administration ( 2.1 )] . Consider testing for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (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 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 dosage of mercaptopurine 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 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 with other hepatotoxic drugs [see Drug Interactions ( 7.5 )] or with known pre-existing liver disease. Withhold mercaptopurine 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 is not indicated for use in inflammatory bowel disease [see Indications and Usage ( 1.1 )] . Discontinue mercaptopurine 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. 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 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 and for 6 months after the last dose. 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 ( 8.1 , 8.3 )] . 5.7 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). Phenylketonuric patients should be informed that mercaptopurine oral suspension contains phenylalanine, a component of aspartame. Each mL of the mercaptopurine oral suspension, 20 mg/mL contains 0.015 mg of phenylalanine.

Kontraindikationen

4 CONTRAINDICATIONS None. • None

Pharmakokinetik

12.3 Pharmacokinetics 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 .

Frequently Asked Questions

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION • 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 …

5 WARNINGS AND PRECAUTIONS • Myelosuppression : Monitor complete blood count (CBC) and adjust the dose of mercaptopurine 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-TPMT or homozygous-NUDT15 deficiency may require a dose reduction. ( 2.2 , 5.1 ) • Hepatotoxicity : Monitor transaminases, alkaline phosphatase and bilirubin. Withhold mercaptopurine at onset of hepatotoxicity. ( 5.2 ) • Immunosuppression : Response …

4 CONTRAINDICATIONS None. • None

Mercaptopurine is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Similar Liquid/Solution Products

Brompheniramine, Pseudoephedrine, Dextromethorphan

Fosfomycin Tromethamine

Diazepam Oral

Lithium Citrate

Erythromycin Ethylsuccinate

Promethazine, Phenylephrine, Codeine

Browse all Liquid/Solution products →

References & Data Sources

• DailyMed — Mercaptopurine drug label (National Library of Medicine)
• openFDA — Mercaptopurine label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 1536484 (NLM Normalized Drug Names)
• NDC Directory — Mercaptopurine (FDA National Drug Code)

Medizinischer Haftungsausschluss

Die Informationen auf dieser Seite dienen ausschließlich zu Bildungszwecken und sollten nicht als Ersatz für professionellen ärztlichen Rat, Diagnose oder Behandlung verwendet werden.

Wenden Sie sich bei Fragen zu einem medizinischen Zustand oder einem Arzneimittel stets an Ihren Arzt oder einen anderen qualifizierten Angehörigen der Gesundheitsberufe.

Datenquellen: DailyMed (NLM), openFDA, MFDS