MERCAPTOPURINE

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 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. 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

None. • None

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.

• Allopurinol : Reduce the dose of mercaptopurine when coadministered with allopurinol. ( 2.4 , 7.1 ) • Warfarin : Mercaptopurine 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 [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 )] .