MERCAPTOPURINE

Mercaptopurine, a nucleoside metabolic inhibitor. The chemical name is 1,7-dihydro-6H-purine-6-thione 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 is a yellow, odorless or practically odorless, crystalline powder. It is practically insoluble in water with pKa 7.8, 11.2. MERCAPTOPURINE oral suspension contains 2,000 mg/100 mL (20 mg/mL) of mercaptopurine. The suspension also contains the following inactive ingredients: xanthan gum, aspartame, concentrated raspberry juice, sucrose, ethyl parahydroxybenzoate sodium, methyl parahydroxybenzoate sodium, potassium sorbate, sodium hydroxide and purified water. MERCAPTOPURINE is a pink to brown viscous suspension. structure

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 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 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 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/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 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 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 and during each visit to the clinic. Advise patients and caregivers to use MERCAPTOPURINE within 8 weeks and properly discard remaining MERCAPTOPURINE after 8 weeks. Provide instructions regarding which syringe to use and how to administer the specified dose, since MERCAPTOPURINE 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. MERCAPTOPURINE is a hazardous drug. Follow special handling and disposal procedures. 1 3 DOSAGE FORMS AND STRENGTHS Oral suspension: 2,000 mg/100 mL (20 mg/mL). ( 3 ) Oral Suspension: 2,000 mg/100 mL (20 mg/mL) pink to brown in color. 4 CONTRAINDICATIONS None None. 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 ) 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) ]. 6 ADVERSE REACTIONS 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 Rare Disease Therapeutics, Inc., at 1-844-472-7389 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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) ] 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 mylelosuppression 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. 7 DRUG INTERACTIONS Allopurinol : Reduce the dose of MERCAPTOPURINE when co-administered with allopurinol. ( 2.4 , 7.1 ) Warfarin : MERCAPTOPURINE may decrease the anticoagulant effect. ( 7.2 ) See FDA approved patient labeling and 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) ]. 8 USE IN SPECIFIC POPULATIONS 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 has 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) ].

None None.

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 Rare Disease Therapeutics, Inc., at 1-844-472-7389 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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) ]

Allopurinol : Reduce the dose of MERCAPTOPURINE when co-administered with allopurinol. ( 2.4 , 7.1 ) Warfarin : MERCAPTOPURINE may decrease the anticoagulant effect. ( 7.2 ) See FDA approved patient labeling and