洛莫司汀胶囊 eeNU 拼音名：Luomositing Jiaonang 英文名：Lomustine Capsules 书页号：2000年版二部－528 本品含洛莫司汀(C9H16ClN3O2) 应为标示量的90.0％～110.0 ％。 【鉴别】 取本品的内容物，照洛莫司汀项下的鉴别(1)、(2)、(4)项试验，显相同的结果。 【检查】 应符合胶囊剂项下有关的各项规定（附录Ⅰ E）。 【含量测定】 避光操作。取装量差异项下的内容物，混合均匀，精密称取适量，照洛莫司汀项下的方法测定，即得。 【类别】 【贮藏】 同洛莫司汀 【规格】 (1) 40mg (2) 100mg 本品主要成份为：洛莫司汀。其化学名称为：N-(2-氯乙基)-N′-环己基-N-亚硝基脲。 分子式：C9H16ClN3O2 分子量：233.70 【药理毒理】本品为细胞周期非特异性药，对处于G2－S边界，或S早期的细胞最敏感，对G2期亦有抑制作用。动物实验表明其与BCNU机理相似。本品进入人体后，其分子从氨甲酰胺键处断裂为两部分：一为氯乙胺部分，将氯解离，形成乙烯碳正离子，发挥烃化作用，致使DNA链断裂，RNA及蛋白质受到烃化，这些主要与抗瘤作用有关；另一为氨甲酰基部分变为异氰酸酯．或再转化为氨甲酸，以发挥氨甲酰化作用，主要与蛋白质，特别是与其中的赖氨酸末端氨基等反应。据认为这主要与骨髓毒性作用有关，氨甲酰化作用还可破坏一些酶蛋白，使DNA受烃化破坏后较难于修复，有助于抗癌作用。本品虽具烷化剂作用。但与一般烷化剂无交叉耐药性，与长春新碱、甲基苄肼及抗代谢药物亦无交叉耐药性。对小鼠和兔子的试验表明该药物有致癌性。 【药代动力学】口服易吸收，体内迅速变为代谢产物。器官分布以肝（胆汁）。肾脾为多，次为肺、心、肌肉、小肠、大肠等。能透过血脑屏障，数分钟后脑脊液中药物浓度为血浆浓度的15～30%，可经胆汁排人肠道，形成肝肠循环，故药效持久。血浆蛋白结合率为50％（代谢物）。T1/2为16～18小时，其持久存在可能引起迟发性骨髓抑制。在肝内代谢完全，排泄于胆汁。有肠肝循环，故药效持久。在尿、血浆、脑脊液均无原形药存在。口服24小时内，本品的50％以代谢物形式从尿中排泄，但4日排泄量小于75%；从粪中排泄少于5%，从呼吸道排出约10％。因其脂溶性强，可有效透过血脑屏障。脑脊液中药物浓度为血浆中的50%或更高。 【适应症】本品脂溶性强，可通过血脑屏障，进入脑脊液，常用于脑部原发肿瘤（如成胶质细胞瘤）及继发性肿瘤；治疗实体瘤，如联合用药治疗胃癌、直肠癌及支气管肺癌、恶性淋巴瘤等。 【用法和用量】100～130mg/m2，顿服，每6～8周一次，3次为一疗程。 【不良反应】口服后6小时内可发生恶心、呕吐，可持续2～3天，预先用镇静药或甲氧氯普胺并空腹服药药可减轻；少数患者发生胃肠道出血及肝功能损害。骨髓抑制，服药后3～5周可见血小板减少，白细胞降低可在服药后第1及第4周先后出现两次，第6～8周才恢复；但骨髓抑制有累计性。偶见全身性皮疹，有致畸胎的可能，亦可能抑制睾丸或卵巢功能，引起闭经或精子缺乏。 【禁忌】有肝功能损害、白细胞低于4×109／l、血小板低于80×109／l者禁用。合并感染时应先治疗感染。 【注意事项】1、因可引起突变和畸变，孕妇及哺乳期妇女应禁用。2、对诊断的干扰：本品可引起肝功能一时性异常。3、下列情况慎用：骨髓抑制、感染、肾功能不全、经过放射治疗或抗癌药治疗的患者或有白细胞低下史者。4、用药期间应注意随访检查血常规及血小板、血尿素氮、血尿酸、肌酐清除率、血胆红素、丙氨酸氨基转移酶等。5、病人宜睡前与止吐药、安眠药共服，用药当天不能饮酒。6、治疗前和治疗中应检查肺功能。 【孕妇及哺乳期妇女用药】本药有致癌、致畸作用，故妊娠及哺乳期妇女禁用。 【儿童用药】100-130mg/m2，顿服，每6～8周重复。 【老年患者用药】 【药物相互作用】 以本品组成联合化疗方案时，应避免合用有严重降低白细胞和血小板的抗癌药。 【药物过量】 尚无药物可对抗药物过量，如出现严重骨髓抑制，白细胞过低可使用粒细胞集落刺激因子。 Generic Name: lomustine Dosage Form: capsule Warnings CeeNU (lomustine) should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to bleeding and overwhelming infections in an already compromised patient, is the most common and severe of the toxic effects of CeeNU (see WARNINGS and ADVERSE REACTIONS). Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the recommended dosage, courses of CeeNU should not be given more frequently than every 6 weeks. The bone marrow toxicity of CeeNU is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under DOSAGE AND ADMINISTRATION). CeeNU Description CeeNU® (lomustine) (CCNU) is one of the nitrosoureas used in the treatment of certain neoplastic diseases. It is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea. It is a yellow powder with the empirical formula of C9H16ClN3O2 and a molecular weight of 233.71. CeeNU is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). CeeNU is relatively insoluble in water (<0.05 mg per mL). It is relatively unionized at a physiological pH. Inactive ingredients in CeeNU Capsules are magnesium stearate and mannitol. The structural formula is: CeeNU is available in 10 mg, 40 mg, and 100 mg capsules for oral administration. CeeNU - Clinical Pharmacology Although it is generally agreed that CeeNU alkylates DNA and RNA, it is not cross resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. CeeNU may be given orally. Following oral administration of radioactive CeeNU at doses ranging from 30 mg/m2 to 100 mg/m2, about half of the radioactivity given was excreted in the urine in the form of degradation products within 24 hours. The serum half-life of the metabolites ranges from 16 hours to 2 days. Tissue levels are comparable to plasma levels at 15 minutes after intravenous administration. Because of the high lipid solubility and the relative lack of ionization at physiological pH, CeeNU crosses the blood-brain barrier quite effectively. Levels of radioactivity in the CSF are 50% or greater than those measured concurrently in plasma. Indications and Usage for CeeNU CeeNU has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination therapy with other approved chemotherapeutic agents in the following: Brain tumors—both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures. Hodgkin’s Disease—secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy. Contraindications CeeNU should not be given to individuals who have demonstrated a previous hypersensitivity to it. Warnings Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the recommended dosage, courses of CeeNU should not be given more frequently than every 6 weeks. The bone marrow toxicity of CeeNU is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under DOSAGE AND ADMINISTRATION). Pulmonary toxicity from CeeNU appears to be dose related (see ADVERSE REACTIONS). Long-term use of nitrosoureas has been reported to be possibly associated with the development of secondary malignancies. Liver and renal function tests should be monitored periodically (see ADVERSE REACTIONS). Pregnancy Category D CeeNU can cause fetal harm when administered to a pregnant woman. CeeNU is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. 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 (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Precautions General In all instances where the use of CeeNU is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of CeeNU therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity. Information for the Patient Patients receiving CeeNU should be given the following information and instructions by the physician: Patients should be told that CeeNU is an anticancer drug and belongs to the group of medicines known as alkylating agents.   In order to provide the proper dose of CeeNU, patients should be aware that there may be 2 or more different types and colors of capsules in the container dispensed by the pharmacist.   Patients should be told that CeeNU is given as a single oral dose and will not be repeated for at least 6 weeks.   Patients should be told that nausea and vomiting usually last less than 24 hours, although loss of appetite may last for several days.   If any of the following reactions occur, notify the physician: fever, chills, sore throat, unusual bleeding or bruising, shortness of breath, dry cough, swelling of feet or lower legs, mental confusion, or yellowing of eyes and skin.   Patients should be told to wear gloves when handling CeeNU Capsules. Laboratory Tests Due to delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose. Baseline pulmonary function studies should be conducted along with frequent pulmonary function tests during treatment. Patients with a baseline below 70% of the predicted Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DLCO) are particularly at risk. Since CeeNU may cause liver dysfunction, it is recommended that liver function tests be monitored periodically. Renal function tests should also be monitored periodically. Carcinogenesis, Mutagenesis, Impairment of Fertility CeeNU is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential in humans (see ADVERSE REACTIONS). CeeNU also affects fertility in male rats at doses somewhat higher than the human dose. Pregnancy Pregnancy Category D See WARNINGS. 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 from CeeNU, 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 ADVERSE REACTIONS: Pulmonary Toxicity, and DOSAGE AND ADMINISTRATION. Geriatric Use No data from clinical studies of CeeNU are available for patients 65 years of age and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Lomustine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored. Adverse Reactions Hematologic Toxicity The most frequent and most serious toxicity of CeeNU is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a dose of CeeNU and persists for 1 to 2 weeks. Approximately 65% of patients receiving 130 mg/m2 develop white blood counts below 5000 wbc/mm3. Thirty-six percent developed white blood counts below 3000 wbc/mm3. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose-limiting toxicities. CeeNU may produce cumulative myelosuppression, manifested by more depressed indices or longer duration of suppression after repeated doses. The occurrence of acute leukemia and bone marrow dysplasias have been reported in patients following long term nitrosourea therapy. Anemia also occurs, but is less frequent and less severe than thrombocytopenia or leukopenia. Pulmonary Toxicity Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported rarely with CeeNU. Onset of toxicity has occurred after an interval of 6 months or longer from the start of therapy with cumulative doses of CeeNU usually greater than 1100 mg/m2. There is one report of pulmonary toxicity at a cumulative dose of only 600 mg. Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received related nitrosoureas in childhood and early adolescence (1–16 years) combined with cranial radiotherapy for intracranial tumors. There appeared to be some late reduction of pulmonary function of all long-term survivors. This form of lung fibrosis may be slowly progressive and has resulted in death in some cases. In this long-term study of carmustine, all those initially treated at less than 5 years of age died of delayed pulmonary fibrosis. Gastrointestinal Toxicity Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually last less than 24 hours. Prior administration of antiemetics is effective in diminishing and sometimes preventing this side effect. Nausea and vomiting can also be reduced if CeeNU is administered to fasting patients. Hepatotoxicity A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline phosphatase and bilirubin levels, has been reported in a small percentage of patients receiving CeeNU. Nephrotoxicity Renal abnormalities consisting of progressive azotemia, decrease in kidney size and renal failure have been reported in patients who received large cumulative doses after prolonged therapy with CeeNU. Kidney damage has also been reported occasionally in patients receiving lower total doses. Other Toxicities Stomatitis, alopecia, optic atrophy, and visual disturbances such as blindness, have been reported infrequently. Neurological reactions, such as disorientation, lethargy, ataxia, and dysarthria have been noted in some patients receiving CeeNU. However, the relationship to medication in these patients is unclear. Overdosage No proven antidotes have been established for CeeNU overdosage. CeeNU Dosage and Administration The recommended dose of CeeNU in adult and pediatric patients as a single agent in previously untreated patients is 130 mg/m2 as a single oral dose every 6 weeks. In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m2 every 6 weeks. When CeeNU is used in combination with other myelosuppressive drugs, the doses should be adjusted accordingly. Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment: Nadir After Prior Dose Percentage of Prior Dose to be Given Leukocytes Platelets >4000 >100,000 100% 3000–3999 75,000–99,999 100% 2000–2999 25,000–74,999 70% <2000 <25,000 50% A repeat course of CeeNU should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm3; leukocytes above 4000/mm3), and this is usually in 6 weeks. Adequate number of neutrophils should be present on a peripheral blood smear. Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks because the hematologic toxicity is delayed and cumulative. How is CeeNU Supplied The dose pack of CeeNU® (lomustine) Capsules, NDC 0015-3034-10, contains:           2—100 mg capsules (Green/Green)           2—40 mg capsules (White/Green)           2—10 mg capsules (White/White) Stability CeeNU Capsules are stable for the lot life indicated on package labeling when stored in well-closed containers at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F) [see USP Controlled Room Temperature]. Avoid excessive heat (over 40°C, 104°F). Directions to the Pharmacist The dose pack contains a total of 300 mg and will provide enough medication for titration of a single dose. The total dose prescribed by the physician can be obtained (to within 10 mg) by determining the appropriate combination of the enclosed capsule strengths. The appropriate number of capsules of each size should be placed in a single vial to which the patient information label (gummed label provided) explaining the differences in the appearance of the capsules is affixed. Each color-coded capsule is imprinted with the dose in milligrams. Caution should be exercised when handling CeeNU Capsules. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing CeeNU Capsules. CeeNU Capsules should not be broken. Personnel should avoid exposure to broken capsules. If contact occurs, wash immediately and thoroughly. More information is available in the references listed below. A patient information sticker, to be placed on dispensing container, is enclosed. Also available: Individual bottles of 20 capsules each.           NDC 0015-3032-20—100 mg capsules (Green/Green)           NDC 0015-3031-20—40 mg capsules (White/Green)           NDC 0015-3030-20—10 mg capsules (White/White) REFERENCES NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd ed.) Pittsburgh, PA: Oncology Nursing Society. Bristol-Myers Squibb Company Princeton, NJ 08543 USA Made in Italy 1050973A3 Rev May 2009 CeeNU  lomustine  kit Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-3034 Packaging # NDC Package Description Multilevel Packaging 1 0015-3034-10 1 KIT In 1 CARTON None QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1 1 BOTTLE   2 CAPSULE  in 1 BOTTLE Part 2 1 BOTTLE   2 CAPSULE  in 1 BOTTLE Part 3 1 BOTTLE   2 CAPSULE  in 1 BOTTLE Part 1 of 3 CeeNU    capsule, gelatin coated Product Information Route of Administration ORAL DEA Schedule      INGREDIENTS Name (Active Moiety) Type Strength lomustine (lomustine) Active 10 MILLIGRAM  In 1 CAPSULE magnesium stearate Inactive   mannitol Inactive   Product Characteristics Color white Score no score Shape CAPSULE Size 16mm Flavor Imprint Code Bristol;3030;10;mg Contains      Coating false Symbol false Packaging # NDC Package Description Multilevel Packaging 1 0015-3030-13 2 CAPSULE In 1 BOTTLE None Part 2 of 3 CeeNU    capsule, gelatin coated Product Information Route of Administration ORAL DEA Schedule      INGREDIENTS Name (Active Moiety) Type Strength lomustine (lomustine) Active 40 MILLIGRAM  In 1 CAPSULE magnesium stearate Inactive   mannitol Inactive   Product Characteristics Color green, white Score no score Shape CAPSULE Size 18mm Flavor Imprint Code Bristol;3031;40;mg Contains      Coating false Symbol false Packaging # NDC Package Description Multilevel Packaging 1 0015-3031-13 2 CAPSULE In 1 BOTTLE None Part 3 of 3 CeeNU    capsule, gelatin coated Product Information Route of Administration ORAL DEA Schedule      INGREDIENTS Name (Active Moiety) Type Strength lomustine (lomustine) Active 100 MILLIGRAM  In 1 CAPSULE magnesium stearate Inactive   mannitol Inactive   Product Characteristics Color green Score no score Shape CAPSULE Size 19mm Flavor Imprint Code Bristol;3032;100;mg Contains      Coating false Symbol false Packaging # NDC Package Description Multilevel Packaging 1 0015-3032-13 2 CAPSULE In 1 BOTTLE None CeeNU  lomustine  capsule, gelatin coated Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-3030 Route of Administration ORAL DEA Schedule      INGREDIENTS Name (Active Moiety) Type Strength lomustine (lomustine) Active 10 MILLIGRAM  In 1 CAPSULE magnesium stearate Inactive   mannitol Inactive   Product Characteristics Color white Score no score Shape CAPSULE Size 16mm Flavor Imprint Code Bristol;3030;10;mg Contains      Coating false Symbol false Packaging # NDC Package Description Multilevel Packaging 1 0015-3030-20 1 BOTTLE In 1 CARTON contains a BOTTLE 1 20 CAPSULE In 1 BOTTLE This package is contained within the CARTON (0015-3030-20) CeeNU  lomustine  capsule, gelatin coated Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-3031 Route of Administration ORAL DEA Schedule      INGREDIENTS Name (Active Moiety) Type Strength lomustine (lomustine) Active 40 MILLIGRAM  In 1 CAPSULE magnesium stearate Inactive   mannitol Inactive   Product Characteristics Color green, white Score no score Shape CAPSULE Size 18mm Flavor Imprint Code Bristol;3031;40;mg Contains      Coating false Symbol false Packaging # NDC Package Description Multilevel Packaging 1 0015-3031-20 1 BOTTLE In 1 CARTON contains a BOTTLE 1 20 CAPSULE In 1 BOTTLE This package is contained within the CARTON (0015-3031-20) CeeNU  lomustine  capsule, gelatin coated Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-3032 Route of Administration ORAL DEA Schedule      INGREDIENTS Name (Active Moiety) Type Strength lomustine (lomustine) Active 100 MILLIGRAM  In 1 CAPSULE magnesium stearate Inactive   mannitol Inactive   Product Characteristics Color green Score no score Shape CAPSULE Size 19mm Flavor Imprint Code Bristol;3032;100;mg Contains      Coating false Symbol false Packaging # NDC Package Description Multilevel Packaging 1 0015-3032-20 1 BOTTLE In 1 CARTON contains a BOTTLE 1 20 CAPSULE In 1 BOTTLE This package is contained within the CARTON (0015-3032-20)