新型抗癌药PURIXAN（巯基嘌呤,mercaptopurine oral suspension）混悬液获美国FDA批准治疗儿童急性淋巴细胞性白血病 2014年5月26日，美国食品药品监督管理局（FDA）批准了一款巯嘌呤的口服混悬剂——Nova实验室旗下药物Purixan，用于治疗急性淋巴细胞性白血病（ALL）。 巯嘌呤在美国以外市场以Xaluprine为商品名上市，但Nova表示，由于其片剂药物需要根据患者（多数为儿童）人体表面积来调整给药剂量，所以导致问题频频出现。该公司在一份声明中这样表示：“口服混悬剂相比片剂，可以提供更加一致的吸收，允许精确的2mg个体化给药。” 支持该药物批准的临床试验证明，Purixan与巯嘌呤片剂具有生物等效性。欧洲药品管理局（EMA）于2012年3月推荐了这款药物，由于其治疗相对罕见的ALL，该药物在美国被授予了孤儿药资格。 根据美国癌症协会提供的信息，2014年美国将有6020名新的ALL患者被确诊，大约有1440名患者会死于这种疾病，这种疾病始于骨髓中的白细胞，在儿童中较为常见。Nova临床开发主管Hussain Mulla博士说：“我们对于FDA的批准感到非常自豪，这将会有助于改善全球儿童癌症患者的治疗 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PURIXAN safely and effectively. See full prescribing information for PURIXAN. PURIXAN (R) (mercaptopurine) oral suspension Initial U.S. Approval: 1953 RECENT MAJOR CHANGES DOSAGE AND ADMINISTRATION, Administration Instructions (2.3)     12/2014 DESCRIPTION (11)      12/2014 HOW SUPPLIED/STORAGE AND HANDLING, How Supplied (16.1)     12/2014 PATIENT COUNSELING INFORMATION (17)      12/2014 PATIENT INFORMATION       12/2014 INSTRUCTIONS FOR USE         12/2014 INDICATIONS AND USAGE PURIXAN (mercaptopurine) is a nucleoside metabolic inhibitor indicated for the treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a combination maintenance therapy regimen. (1.1) DOSAGE AND ADMINISTRATION The starting dose of PURIXAN in multi-agent combination chemotherapy maintenance regimens is 1.5 to 2.5 mg/kg (50 to 75 mg/m2) as a single daily dose. Use absolute neutrophil count to guide dosing. (2.1) DOSAGE FORMS AND STRENGTHS Oral suspension: 2000 mg/100 mL (20 mg/mL). (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS Myelosuppression: Monitor complete blood count (CBC) and adjust the dose of PURIXAN for severe neutropenia and thrombocytopenia. Evaluate patients with repeated severe myelosuppression for thiopurine S-methyltransferase (TPMT) deficiency. Patients with homozygous-TPMT deficiency require substantial dose reductions of PURIXAN. (5.1) Hepatotoxicity: Monitor transaminases and bilirubin. Hold or adjust the dose of PURIXAN. (5.2) Immunosuppression: 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 children. (5.3) Embryo-fetal toxicity: PURIXAN can cause fetal harm. Advise women of potential risk to a fetus. (5.4) ADVERSE REACTIONS The most frequent adverse reaction (> 20% of patients) is myelosupression including anemia, neutropenia, and thrombocytopenia. Less common (5-20% of patients) adverse reactions include elevated transaminases, elevated bilirubin, intestinal ulceration, nausea, vomiting, anorexia, diarrhea and rashes. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Rare Disease Therapeutics, Inc., at 1 888-470-0904 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Allopurinol: Avoid use (7.1) Warfarin: PURIXAN may inhibit the anticoagulant effect. (7.2) See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1. INDICATIONS AND USAGE 1.1 Acute Lymphoblastic Leukemia PURIXAN (mercaptopurine) is indicated for the treatment of patients with acute lymphoblastic leukemia as part of a combination regimen.  2. DOSAGE AND ADMINISTRATION 2.1 Maintenance Therapy The starting dose of PURIXAN in multi-agent combination chemotherapy maintenance regimens is 1.5 to 2.5mg/kg (50 to 75 mg/m2) as a single daily dose. After initiating PURIXAN, continuation of appropriate dosing requires periodic monitoring of absolute neutrophil count (ANC) and platelet count to assure sufficient drug exposure (that is to maintain ANC at a desirable level) and to adjust for excessive hematological toxicity. 2.2 Dosage in TPMT-deficient Patients Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe mercaptopurine toxicity from conventional doses of mercaptopurine and generally require dose reduction. Testing for TPMT gene polymorphism should be considered in patients who experience severe bone marrow toxicities [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.5)]. Homozygous deficient patients may require up to a 90% dosage reduction (10% of the standard PURIXAN dose). Most patients with heterozygous TPMT deficiency tolerated recommended mercaptopurine doses, but some require dose reduction based on toxicities. 2.3 Administration Instructions Prior to initiation of Purixan and on each visit to the clinic, train patients or caregivers on proper handling, storage, administration, disposal and clean-up of accidental spillage of the medication. Since Purixan is supplied with 1 mL and 5 mL oral dispensing syringes, provide appropriate instructions regarding which syringe to use and how to administer a specified dose. The bottle should be shaken vigorously for at least 30 seconds to ensure the oral suspension is well mixed. PURIXAN is a pink to brown viscous oral suspension. Once opened, PURIXAN should be used within 6 weeks. A press-in bottle adapter and two oral dispensing syringes (one 1 mL and one 5 mL) are provided. The oral dispensing syringe is intended for multiple use: 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 for dosing; and store the oral dispensing syringe in a hygienic place with the medicine. PURIXAN is a cytotoxic drug. Follow special handling and disposal procedures.1 3. DOSAGE FORMS AND STRENGTHS Oral Suspension: 2000 mg/100 mL (20 mg/mL) - pink to brown in color. 4. CONTRAINDICATIONS None. 5. WARNINGS AND PRECAUTIONS 5.1 Myelosuppression The most consistent, dose-related toxicity of PURIXAN is bone marrow suppression, manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. Monitor CBC and adjust the dose of PURIXAN for severe neutropenia and thrombocytopenia. Evaluate patients with repeated severe myelosuppression for thiopurine S-methyltransferase (TPMT) deficiency. Patients with homozygous-TPMT deficiency require substantial dose reductions of PURIXAN [see Dosage and Administration (2.1), and Clinical Pharmacology (12.5)]. Avoid the concurrent use of allopurinol and PURIXAN. Concomitant allopurinol and PURIXAN can result in a significant increase in bone marrow toxicity. Myelosuppression can be exacerbated by coadministration with drugs that inhibit TPMT (e.g., olsalazine, mesalamine, or sulfasalazine) or drugs whose primary or secondary toxicity is myelosuppression [see Drug Interactions (7.1, 7.3 and 7.4)]. 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 the start of treatment with mercaptopurine. The hepatotoxicity has been associated in some cases with anorexia, diarrhea, jaundice and ascites. 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 function more frequently in patients who are receiving mercaptopurine with other hepatotoxic drugs or with known pre-existing liver disease. Interrupt PURIXAN in patients with onset of clinical or laboratory evidence of hepatotoxicity. 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 children. 5.4 Embryo-Fetal Toxicity PURIXAN can cause fetal harm when administered to a pregnant woman. Women receiving PURIXAN in the first trimester of pregnancy have an increased incidence of abortion. Adverse embryo-fetal findings were reported in women receiving mercaptopurine after the first trimester of pregnancy and included abortion and stillbirth. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving PURIXAN [see Use in Specific Populations (8.1)]. 5.5 Treatment Related Malignancies Cases of hepatosplenic T-cell lymphoma have been reported in patients treated with mercaptopurine for inflammatory bowel disease, for which mercaptopurine is not approved. Mercaptopurine is mutagenic in animals and humans, carcinogenic in animals, and may increase the risk of secondary malignancies. 5.6 Laboratory Tests Monitor the following laboratory tests in patients receiving PURIXAN: Complete blood counts (CBCs), transaminases, and bilirubin. Evaluate the bone marrow in patients with prolonged or repeated marrow suppression to assess leukemia status and marrow cellularity. Evaluate TPMT status in patients with clinical or laboratory evidence of severe bone marrow toxicity, or repeated episodes of myelosuppression. 6. ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the prescribing information: Myelosuppression [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Immunosuppression [see Warnings and Precautions (5.3)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.4)] Treatment Related Malignancies [see Warnings and Precautions (5.5)] 6.1 Clinical Studies 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 is mylelosuppression including anemia, neutropenia, lymphopenia and thrombocytopenia. Adverse reactions occurring 5 to 20 % include anorexia, nausea, vomiting, diarrhea, malaise, and rash. Rare adverse reactions occuring < 5 % include urticaria, hyperuricemia, oral lesions, elevated transaminases, hyperbilirubinemia, hyperpigmentation, 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 and 5.2)]. Drug fever has been very rarely reported with PURIXAN. Before attributing fever to PURIXAN, every attempt should be made to exclude more common causes of pyrexia, such as sepsis, in patients with acute leukemia. 7. DRUG INTERACTIONS Certain drugs have been shown to interact with PURIXAN through pharmacokinetic and pharmacodynamic mechanisms. Interactions known to decrease the clearance of PURIXAN include inhibition of first-pass oxidative metabolism by xanthine oxidase and inhibition of thiopurine methyltransferase (TPMT). Consult the labeling of all concurrently used drugs to obtain further information about drug interactions with PURIXAN. 7.1 Allopurinol Avoid concomitant use of PURIXAN and allopurinol. Concomitant use of allopurinol with PURIXAN inhibits the first-pass oxidative metabolism of mercaptopurine by xanthine oxidase, leading to mercaptopurine toxicity (bone marrow suppression, nausea, vomiting) [see Warnings and Precautions (5.1)]. 7.2 Warfarin Concurrent use of PURIXAN and warfarin may result in decreased anticoagulant effectiveness. Monitor prothrombin time or international normalized ratio (INR) in patients receiving oral anticoagulant therapy with warfarin. Adjustments of the warfarin dose may be necessary in order to maintain the desired level of anticoagulation. 7.3 Myelosuppressants Bone marrow suppression may be increased when PURIXAN is combined with other drugs whose primary or secondary toxicity is myelosuppression. Enhanced marrow suppression has been noted in some patients also receiving trimethoprim-sulfamethoxazole. Monitor CBC and adjust the dose of PURIXAN for severe neutropenia and thrombocytopenia [see Warnings and Precautions (5.1)]. 7.4 Aminosalicylate Derivatives Concurrent use of PURIXAN and aminosalicylate derivatives (e.g., olsalazine, mesalamine, or sulfasalazine) may inhibit the TPMT enzyme, resulting in an increased risk of bone marrow suppression. Should aminosalicylate derivatives and PURIXAN be coadministered, use the lowest possible doses of each drug and closely monitor the patient for bone marrow suppression [see Warnings and Precautions (5.1)]. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.4)]. Risk Summary PURIXAN can cause fetal harm when administered to a pregnant woman. Women receiving PURIXAN have an increased incidence of abortion and stillbirth. Advise women to avoid becoming pregnant while receiving PURIXAN. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Human Data Women receiving mercaptopurine in the first trimester of pregnancy have an increased incidence of abortion; 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 delivered, 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). 8.3 Nursing Mothers It is not known whether mercaptopurine is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from mercaptopurine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of mercaptopurine for the treatment of ALL in pediatric patients have not been established in adequate and well-controlled trials. The evidence for efficacy of mercaptopurine is derived from the published literature and clinical experience. The toxicities of mercaptopurine are similar in adults and children. 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 other drug therapy. 8.6 Renal Impairment No formal clinical or pharmacokinetic studies have been conducted in patients with renal impairment. Starting at the low end of the PURIXAN dosing range, or increasing the dosing interval to 36-48 hours can be considered in patients with baseline renal impairment. Subsequent PURIXAN doses should be adjusted based on efficacy and toxicity [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)]. 8.7 Hepatic Impairment No formal clinical or pharmacokinetic studies have been conducted in patients with hepatic impairment. Mercaptopurine is hepatotoxic. In patients with baseline hepatic impairment, starting at the low end of the PURIXAN dose range should be considered and patients should be monitored for toxicity [see Dosage and Administration (2.1) and Warnings and Precautions (5.1, 5.2)].  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. The oral LD50 of mercaptopurine was determined to be 480mg/kg in the mouse and 425mg/kg in the rat. There is no known pharmacologic antagonist of mercaptopurine. PURIXAN should be discontinued immediately if unintended toxicity occurs during treatment. If a patient is seen immediately following an accidental overdosage of PURIXAN, it may be useful to induce emesis. 11. DESCRIPTION Mercaptopurine, a nucleoside metabolic inhibitor, known chemically as 1,7-dihydro-6H-purine-6-thione monohydrate, is an analogue of the purine bases adenine and hypoxanthine. Mercaptopurine is a yellow, odorless or practically odorless, crystalline powder with a molecular formula of C5H4N4S•H2O and a molecular weight of 170.20 as a monohydrate. The structural formula is: PURIXAN (mercaptopurine) oral suspension is supplied for oral administration and contains 2000 mg/100 mL (20 mg/mL) of mercaptopurine. The suspension also contains the following inactive ingredients: xanthan gum, aspartame, concentrated raspberry juice, sucrose, methyl parahydroxybenzoate, propyl parahydroxybenzoate and purified water. PURIXAN is a pink to brown viscous suspension. In addition, a press-in bottle adapter and two oral dispensing syringes (one 1 mL and one 5 mL) are provided. 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Mercaptopurine activation occurs via hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) and several enzymes to form 6-thioguanine nucleotides (6-TGNs). Incorporation of 6-TGN into nucleic acids (instead of purine bases) results in cell-cycle arrest and cell death. Mercaptopurine competes with hypoxanthine and guanine for HGPRTase and is itself converted to thioinosinic acid (TIMP). This intracellular nucleotide inhibits several reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP). 12.3 Pharmacokinetics The relative bioavailability of PURIXAN was compared to mercaptopurine 50 mg tablets in 62 healthy subjects in a single-dose, two-period, crossover study under fasting conditions. Bioequivalence was demonstrated based on the primary PK parameters AUC(0-t) and AUC(0-∞). Cmax did not demonstrate bioequivalence. The mean Cmax following PURIXAN administration was 34% higher than the tablet. Absorption and Bioavailability Clinical studies have shown that the absorption of an oral dose of mercaptopurine in humans is incomplete and variable, averaging approximately 50% of the administered dose. The factors influencing absorption are unknown. Following a single 50 mg dose of PURIXAN under fasting conditions the median (range) AUC was 136 h*ng/mL (74.2-264.8 h*ng/mL) and Cmax was 95 ng/mL (39.5-204 ng/mL). Distribution The volume of distribution usually exceeded that of the total body water. There is negligible entry of mercaptopurine into cerebrospinal fluid. 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 Following administration of PURIXAN, the elimination half-life (t1/2) was approximately 2 hours. 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. 12.5 Pharmacogenomics TPMT enzyme activity is highly variable in patients because of a genetic polymorphism in the TPMT gene. For Caucasians and African Americans, approximately 0.3% (1:300) of patients have two non-functional alleles (homozygous-deficient) of the TPMT gene and have little or no detectable TMPT activity. Approximately 10% of patients have one TPMT non-functional allele (heterozygous) leading to low or intermediate TPMT activity and 90% of patients have normal TPMT activity with two functional alleles. Homozygous-deficient patients with little or no detectable TPMT activity, if given usual doses of mercaptopurine, accumulate excessive cellular concentrations of active 6-TGNs predisposing them to mercaptopurine toxicity. Heterozygous patients with low or intermediate TPMT activity accumulate higher concentrations of active 6-TGNs than patients with normal TPMT activity and are more likely to experience mercaptopurine toxicity [see Warnings and Precautions (5.1)]. TPMT genotyping or phenotyping (red blood cell TPMT activity) can identify patients who are homozygous deficient or have low or intermediate TPMT activity. TPMT Testing Genotypic and phenotypic testing of TPMT status are available. Genotypic testing can determine the allelic pattern of a patient. Currently, 3 alleles—TPMT*2, TPMT*3A and TPMT*3C— account for about 95% of individuals with reduced levels of TPMT activity. Individuals homozygous for these alleles are TPMT deficient and those heterozygous for these alleles have variable TPMT (low or intermediate) activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in erythrocytes and can also be informative. Caution must be used with phenotyping since some coadministered drugs can influence measurement of TPMT activity in blood, and recent blood transfusions will misrepresent a patient’s actual TPMT activity. 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Mercaptopurine is carcinogenic in animals and humans. Mercaptopurine causes chromosomal aberrations in animals and humans and induces dominant-lethal mutations in male mice. Mercaptopurine may 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. 14. CLINICAL STUDIES The safety and effectiveness of mercaptopurine for the treatment of ALL in pediatric and adult patients have not been established in adequate and well-controlled trials. [see Clinical Pharmacology (12.3)].  15. REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on March 28, 2014, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] 16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied PURIXAN (mercaptopurine) oral suspension 2000 mg/100 mL (20 mg/mL) is a pink to brown viscous liquid supplied in amber glass multiple-dose bottles with a child resistant closure. In addition, a press-in bottle adapter and two oral dispensing syringes (one 1 mL and one 5 mL) are provided. 100 mL bottle NDC #62484-0020-1. 16.2 Storage and Handling Store PURIXAN between 59º to 77ºF (15º to 25ºC), in a dry place. Do not store above 25°C. Store the oral dispensing syringe in a clean place, with the medicine. PURIXAN oral suspension should be used within 6 weeks after opening the bottle. Dispose of (throw away) any unused medicine after 6 weeks. Do not use after the expiry date which is stated on the carton and the bottle after ‘EXP’. Keep the bottle tightly closed to prevent spoilage of the medicine and reduce the risk of accidental spillage. Keep PURIXAN and all medicines out of the reach of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children. PURIXAN is a cytotoxic drug. Follow special handling and disposal procedures1. 17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use). Patient Training Prior to initiation of Purixan and on each visit to the clinic, train patients or caregivers on proper handling, storage, administration, and disposal and clean-up of accidental spillage of the medication. Specifically, since Purixan is supplied with 1 mL and 5 mL oral dispensing syringes, provide appropriate instructions regarding which syringe to use and how to administer a specified dose. Major Toxicities Inform patients and caregivers that the major toxicities of PURIXAN are related to myelosuppression, hepatotoxicity, and gastrointestinal toxicity. Advise patients to contact their physician if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia. Pregnancy Advise women of childbearing potential to avoid becoming pregnant. Administration See FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients and caregivers to select the 1 mL or 5 mL syringe whichever is appropriate to deliver the correct dose. Infom patients and caregivers to shake the bottle vigorously for at least 30 seconds to ensure the oral suspension is well mixed. PURIXAN (mercaptopurine) oral suspension is pink in color but because it contains a natural fruit extract, the color of the suspension may vary from pink to brown. Instruct patients and caregivers that once opened, PURIXAN should be used within 6 weeks. Inform patients and caregivers that the oral dispensing syringe is intended for multiple use: 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 for dosing; and store the oral dispensing syringe in a hygienic place with the medicine. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9fd27952-7787-47d9-b6cf-7af2dc38217b