PURINETHOL® (mercaptopurine) 50-mg Scored Tablets CAUTION PURINETHOL (mercaptopurine) is a potent drug. It should not be used unless a diagnosis of acute lymphatic leukemia has been adequately established and the responsible physician is experienced with the risks of purinethol and knowledgeable in assessing response to chemotherapy. DRUG DESCRIPTIONPURINETHOL (mercaptopurine) was synthesized and developed by Hitchings, Elion, and associates at the Wellcome Research Laboratories.Mercaptopurine, known chemically as 1,7-dihydro-6H-purine-6-thione monohydrate, is an analogue of the purine bases adenine and hypoxanthine. Its structural formula is:PURINETHOL is available in tablet form for oral administration. Eachscored tablet contains 50 mg mercaptopurine and the inactive ingredients corn and potato starch, lactose, magnesium stearate, and stearic acid.INDICATIONSPURINETHOL (mercaptopurine) is indicated for maintenance therapy of acute lymphatic (lymphocytic, lymphoblastic) leukemia as part of a combination regimen.. The response to this agent depends upon the particular subclassification of acute lymphatic leukemia and the age of the patient (pediatric or adult).PURINETHOL is not effective for prophylaxis or treatment of central nervous system leukemia.PURINETHOL is not effective in acute myelogenous leukemia, chronic lymphatic leukemia, the lymphomas (including Hodgkins Disease), or solid tumors. DOSAGE AND ADMINISTRATIONMaintenanceTherapy: Once a complete hematologic remission is obtained, maintenance therapy is considered essential. Maintenance doses will vary from patient to patient. The usual daily maintenance dose of PURINETHOL is 1.5 to 2.5 mg/kg/day as a single dose. It is to be emphasized that in pediatric patients with acute lymphatic leukemia in remission, superior results have been obtained when PURINETHOL has been combined with other agents (most frequently with methotrexate) for remission maintenance. PURINETHOL should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia.Procedures for proper handling and disposal of anticancer drugs should be considered.Several guidelines on this subject have beenpublished.1-8 There is no general agreement that alloftheprocedures recommended in the guidelines arenecessaryorappropriate. Dosage with concomitant Allopurinol:When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one third to one quarter of the usual dose to avoid severe toxicity.Dosage in TPMT-deficient Patients: Patientswithinherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe PURINETHOL toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established. (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections.)Most patients with heterozygous TPMT deficiency tolerated recommended PURINETHOL doses, but some require dose reduction. Genotypic and phenotypic testing of TPMT status are available. (See CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections).Dosage in Renal and Hepatic Impairment: It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a greater cumulative effect. Consideration should be given to reducing the dosage in patients with impaired hepatic function.HOW SUPPLIEDPale yellow to buff, scoredtabletscontaining 50 mg mercaptopurine, imprinted with “PURINETHOL” and “04A”; bottles of 25 (NDC 57844-522-07) and 250 (NDC 57844-522-52).Store at 15° to 25°C (59° to 77°F) in a dry place. REFERENCES 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society;1999:32-41. 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety; Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health; 1992. US Dept of Health and Human Services. Public Health Service publication NIH 92-2621. 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591. 4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428. 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clinicians. 1983;33:258-263. 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685. Manufactured for: GATEPHARMACEUTICALS div. of Teva Pharmaceuticals USA, Sellersville, PA 18960.ManufacturedbyDSMPharmaceuticals, Inc. Greenville, NC 27834, Rev. 8/2003. FDA revision date: 7/15/2004 SIDE EFFECTS The principal and potentially serious toxic effects of PURINETHOL are bone marrow toxicity and hepatotoxicity (see WARNINGS and PRECAUTIONS). Hematologic: The most frequent adverse reaction to PURINETHOL is myelosuppression. The induction of complete remission of acute lymphatic leukemia frequently is associated with marrow hypoplasia.Patients without TPMT enzyme activity (homozygous-deficient) are particularly susceptible to hematologic toxicity, and some patients with low or intermediate TPMT enzyme activity are more susceptible to hematologic toxicity than patients with normal TPMT activity (See WARNINGS: Bone Marrow Toxicity),although the latter can also experience severe toxicity. Maintenance of remission generally involves multiple-drugregimenswhosecomponentagentscausemyelosuppression. Anemia, leukopenia, and thrombocytopenia are frequently observed. Dosages and also schedules are adjusted to prevent life-threatening cytopenias.Renal: Hyperuricemia and/or hyperuricosuria may occur in patients receiving PURINETHOL as a consequence of rapid cell lysis accompanying the antineoplastic effect. Renal adverse effects can be minimized by increased hydration, urine alkalinization, and the prophylactic of a xanthine oxidase inhibitor such as allopurinol. The dosage of PURINETHOL should be reduced to one third to one quarter of the usual dose if allopurinol is given concurrently. Gastrointestinal: Intestinal ulceration hasbeenreported. Nausea,vomiting, and anorexia are uncommon duringinitial administration, but may increase with continued administration. Mild diarrhea and sprue-like symptoms have been noted occasionally, but it is difficult at present toattribute these to the medication. Oral lesions are rarely seen, and when they occur they resemble thrush rather than antifolic ulcerations.Miscellaneous:,The administration of PURINETHOL has been associated with skin rashes and hyperpigmentation. Alopecia has been reported. Drug fever has been very rarely reported with PURINETHOL. Before attributing fever to PURINETHOL, every attempt should be made to exclude more common causes of pyrexia, such as sepsis, inpatientswithacuteleukemia.Oligospermia has been reported. DRUG INTERACTIONSWhen allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one third to one quarter of the usual dose to avoid severe toxicity. There is usually complete cross-resistance between mercaptopurine and thioguanine.Thedosageofmercaptopurine may need to be reduced when this agent 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.Inhibition of the anticoagulant effect of warfarin, when given with mercaptopurine, has been reported.As there is in vitro evidence that aminosalicylate derivatives(e.g.,olsalazine,mesalazine,orsulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent mercaptopurine therapy (see WARNINGS).WARNINGSBone Marrow Toxicity: The most consistent, dose-related toxicity is bone marrow suppression. This may bemanifestbyanemia,leukopenia,thrombocytopenia, or any combination of these. Any of these findings may also reflect progression of the underlying disease. In many patients with severe depression of the formed elements of the blood due to PURINETHOL, the bone marrow appears hypoplastic on aspiration or biopsy, whereas in other cases it may appear normocellular. The qualitative changes in the erythroid elements toward the megaloblastic series, characteristically seen with the folic acid antagonists and someotherantimetabolites,arenotseenwiththisdrug.Lifethreateninginfectionsandbleedinghavebeenobservedasaconsequenceofmercaptopurine-induced granulocytopenia and thrombocytopenia. Since mercaptopurine may have a delayed effect, it isimportant to withdraw the medication temporarily at the first sign of an unexpected abnormally large fall in any of the formed elements of the blood, if not attributable to another drug or disease process.Individuals who are homozygous for an inherited defect in the TPMT (thiopurine-S-methyltransferase) gene are unusually sensitive to the myelosuppressiveeffectsofmercaptopurine and prone to developing rapid bone marrow suppression following the initiation of treatment. Laboratory tests are available, both genotypic and phenotypic, to determine the TPMT status. Substantial dose reductions are generally required for homozygous-TPMT deficiency patients (two non functional alleles) to avoid the development of life threatening bone marrow suppression. Although heterozygous patients with intermediate TPMT activity may have increased mercaptopurine toxicity, this is variable, and the majority of patients tolerate normal doses ofPURINETHOL. If a patient has clinical or laboratory evidence of severe toxicity, particularly myelosuppression, TPMT testing should be considered. In patients who exhibit excessive myelosuppression due to 6-mercaptopurine, it may be possible to adjust the mercaptopurine dose and administer the usual dosage of other myelosuppressive chemotherapy as required for treatment (see DOSAGE AND ADMINITRATION).Bone marrow toxicity may be more profound in patients treated with concomitant allopurinol (see PRECAUTIONS: DRUG INTERACTIONS and DOSAGE AND ADMONISTRATION). This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, or sulphasalazine. Hepatotoxicity: Mercaptopurine is hepatotoxic in animals and humans. A small number of deaths have been reported that may have been attributed to hepatic necrosis due to administration of mercaptopurine. Hepatic injury can occur with any dosage, but seems to occur with more frequency when doses of 2.5 mg/kg/day are exceeded. The histologic pattern of mercaptopurine hepatotoxicity includes features of both intrahepatic cholestasis and parenchymal cell necrosis, either of which may predominate. It is not clear how much of the hepatic damage is due to direct toxicity from the drug and how much may be due to a hypersensitivity reaction. In some patients jaundice has cleared following withdrawal of mercaptopurine and reappeared with its reintroduction.Published reports have cited widely varying incidences of overt hepatotoxicity. In a large series of patients with various neoplastic diseases, mercaptopurine was administered orally in doses ranging from 2.5 mg/kg to 5.0 mg/kg without evidence of hepatotoxicity. It was noted by the authors that no definite clinical evidence of liver damage could be ascribed to the drug, although an occasional case of serum hepatitis did occur in patients receiving 6-MP who previously had transfusions. In reports of smaller cohorts of adult and pediatric leukemic patients, the incidence of hepatotoxicity ranged from 0% to 6%. In an isolated report by Einhorn and Davidsohn, jaundice was observed more frequently (40%), especially when doses exceeded 2.5 mg/kg. 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.Monitoring of serum transaminase levels, alkaline phosphatase, and bilirubin levels may allow early detection of hepatotoxicity. It is advisable to monitor these liver function tests at weekly intervals when first beginning therapy and at monthly intervals thereafter. Liver function tests may be advisable more frequently in patients who are receiving mercaptopurine with other hepatotoxic drugs or with known pre-existing liver disease. The onset of clinical jaundice, hepatomegaly, or anorexia with tenderness in the right hypochondrium are immediate indications for withholding mercaptopurine until the exact etiology can be identified. Likewise, any evidence of deterioration in liver function studies, toxichepatitis,orbiliarystasisshouldpromptdiscontinuation of the drug and a search for an etiology of the hepatotoxicity. The concomitant administration of mercaptopurine with other hepatotoxic agents requires especially careful clinical and biochemical monitoring of hepatic function. Combination therapy involving mercaptopurine with other drugs not felt to be hepatotoxic should nevertheless be approached with caution. The combination of mercaptopurine with doxorubicin was reported to be hepatotoxic in 19 of 20 patients undergoing remission-induction therapy for leukemia resistant to previous therapy. Immunosuppression: Mercaptopurine recipients may manifest decreased cellular hypersensitivities and decreased allograft rejection. Induction of immunity to infectious agents or vaccines will be subnormal in these patients; the degree of immunosuppression will depend on antigen dose and temporal relationship to drug. This immunosuppressive effect should be carefully considered with regard to intercurrent infections and risk of subsequent neoplasia. Pregnancy: Pregnancy Category D. Mercaptopurine can cause fetal harm when administered to a pregnant woman. 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 accurately known. In a series of 28 women receiving mercaptopurine after the first trimester of pregnancy, 3 mothers died undelivered, 1 delivered a stillborn child, and 1 aborted; there were no cases of experience cannot exclude the possibility of fetal damage, mercaptopurine should be used during pregnancy only if the benefit clearly justifies the possible risk to the fetus, and particular caution should be given to the use of mercaptopurine in the first trimester of pregnancy. 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 the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. PRECAUTIONSGeneral: Thesafe and effective use of PURINETHOL demands close monitoring of the CBC and patient clinical status. After selection of an initial dosage schedule, therapy will frequently need to be modified depending upon the patient's response and manifestations of toxicity. It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a greater cumulative effect.Laboratory Tests: (Also see WARNINGS, Bone Marrow Toxicity) It is recommended that evaluation of the hemoglobin or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained weekly while the patient is on therapy with PURINETHOL. Bone marrow examination may also be useful for the evaluation of marrow status. The decision to increase, decrease, continue, or discontinue a given dosage of PURINETHOL must be based upon the degree of severity and rapidity with which changes are occurring. In many instances, particularly during the induction phase of acute leukemia, complete blood counts will need to be done more frequently than once weekly in order to evaluate the effect of the therapy. If a patient has clinical or laboratory evidence of severe bone marrow toxicity, particularly myelosuppression, TPMT testing should be considered.TPMT TestingGenotypic 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 co-administered drugs can influence measurement of TPMT activity in blood, and recent blood transfusions will misrepresent a patient's actual TPMT activityCarcinogenesis, Mutagenesis, Impairment of Fertility: Mercaptopurine causes chromosomal aberrations in animals and humans and induces dominant-lethal mutations in male mice. 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. Carcinogenic potential exists in humans, but the extent of the risk is unknown.The effect of mercaptopurine on human fertility is unknown for either males or females.Pregnancy: Teratogenic Effects: Pregnancy Category D. See WARNINGS section.Nursing Mothers: It is not known whether this drug 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 frommercaptopurine, 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.Pediatric Use: See DOSAGE AND ADMINISTRATION section.Geriatric Use:Clinical studies of PURINETHOL 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. 英文药名: Purinethol (mercaptopurine tablets) 中文药名: 巯嘌呤片 生产厂家: Glaxo Smith Kline 通用名：巯嘌呤片 英文名：Mercaptopurine  Tablits 拼音名：QIUPIAOLING PIAN 药品类别：抗代谢类抗肿瘤药 性状 本品为淡黄色片 药理毒理 属于抑制嘌呤合成途径的细胞周期特异性药物，化学结构与次黄嘌呤相似， 因而能竞争性地抑制次黄嘌呤的转变过程。 本品进入体内，在细胞内必须由磷酸 核糖转移酶转为6－巯基嘌呤核糖核苷酸后，方具有活性。 其主要的作用环节有 二：   （1）通过负反馈作用抑制酰胺转移酶，因而阻止1－焦磷酸－5－磷酸核糖 （PRPP）转为1－氨基－5－磷酸核糖（PRA）的过程，干扰了嘌呤核苷酸合成的 起始阶段。   （2）抑制复杂的嘌呤间的相互转变，即能抑制次黄嘌呤核苷酸转为腺 嘌呤核苷酸及次黄嘌呤核苷酸转为黄嘌呤核苷酸、鸟嘌呤核苷酸的过程，同时本 品还抑制辅酶I（NAD+）的合成，并减少了生物合成DNA所必需的脱氧三磷酸腺苷（dATP）及脱氧三磷酸鸟（dGTP），因而肿瘤细胞不能增殖，本品对处于S 增殖周期的细胞较敏感，除能抑制细胞DNA的合成外，对细胞RNA的合成亦有轻 度的抑制作用。用巯嘌呤治疗白血病常产生耐药现象，其原因可能是体内出现了 突变的白血病细胞株，因而失去了将巯嘌呤变为巯嘌呤核糖核苷酸的能力。 药代动力学 口服胃肠道吸收不完全，约50% 。广泛分布于体液内。血浆蛋白结合率约 为20%。本品吸收后的活化分解代谢过程主要在肝脏内进行，在肝内经黄嘌呤氧 化酶等氧化及甲基化作用后分解为硫尿酸等而失去活性。静脉注射后的半衰期约 为90钟，约半量经代谢后在24小时即迅速从肾脏排泄，其中7～39%以原药排 出。 适应症 适用于绒毛膜上皮癌，恶性葡萄胎，急性淋巴细胞白血病及急性非淋巴细胞白血病，慢性粒细胞白血病的急变期。 用法用量 1、绒毛膜上皮癌：成人常用量，每日6mg～6.5mg/kg，分两次口服，以10 日为一疗程，疗程间歇为3～4周。 2、白血病：（1）开始，每日2.5mg/kg或80～100mg/m2，一日1次或分次服用，一般于用药后2～4周可见显效，如用药4周后，仍未见临床改进及白细胞数下降，可考虑在仔细观察下，加量至每日5mg/kg；(2)维持，每日1.5mg～ 2.5mg/kg或50mg～100mg/m2，一日1次或分次口服。 不良反应 1、较常见的为骨髓抑制：可有白细胞及血小板减少； 2、肝脏损害：可致胆汁郁积出现黄疸； 3、消化系统：恶心、呕吐、食欲减退、口腔炎、腹泻，但较少发生，可见 于服药量过大的患者。 4、高尿酸血症：多见于白血病治疗初期，严重的可发生尿酸性肾病； 5、间质性肺炎及肺纤维化少见。 禁忌症 已知对本品高度过敏的患者禁用。 注意事项 1、对诊断的干扰：白血病时有大量白血病细胞破坏，在服本品时则破坏更多，致使血液及尿中尿酸浓度明显增高，严重者可产生尿酸盐肾结石； 2、下列情况应慎用：骨髓已有显著的抑制现象，（白细胞减少或血小板显著 降低）或出现相应的严重感染或明显的出血倾向；肝功能损害、胆道疾患者、有痛风病史、尿酸盐肾结石病史者；4～6周内已接受过细胞毒药物或放射治疗者； 3、用药期间应注意定期检查外周血象及肝、肾功能，每周应随访白细胞计 数及分类、血小板计数、血红蛋白1～2次，对血细胞在短期内急骤下降者，应每日观察血象。 孕妇及哺乳期妇女用药 本品有增加胎儿死亡及先天性畸形的危险，故孕期禁用。 儿童用药 小儿常用量：每日1.5mg～2.5mg/kg或50mg/m2，一日1次或分次口服。老年患者用药由于老年患者对化疗药物的耐受性差，服用本品时，需加强支持疗法，并严 密观察症状、体征及周围血管等的动态改变。 药物相互作用 1、与别嘌呤同时服用时，由于后者抑制了巯嘌呤的代谢，明显地增加巯嘌 呤的效能与毒性； 2、本品与对肝细胞有毒性的药物同时服用时，有增加对肝细胞毒性的危险； 3、本品与其他对骨髓有抑制的抗肿瘤药物或放射治疗合并应用时，会增强 巯嘌呤效应，因而必须考虑调节本品的剂量与疗程。 药物过量 贮藏：遮光、密封保存