Mitotane (米托坦)
【别名】氯苯二氯乙烷、曼托坦、密妥坦 (米托坦) 解腺瘤片,解腺瘤、Chloditan、Chlonlithane。
商品牌子名：LYSODREN TAB 500MG
药物製造商：Bristol-Myers Squibb
剂型：药片
孕妇用药分级：C
【药理】本品结构与杀虫药DDT和DDD相似，可使肾上腺皮质萎缩和坏死。给予本品后可使体内肾上腺皮质激素及其代谢产物水平迅速下降，可用于肾上腺瘤或肾上腺增生引起的枯氏综合征。
口服约40%由胃肠道吸收，其余60%以原型随粪便排出。每日5～10g，血药浓度可达10～90μg/ml，代谢物浓度30～50。停药6～9μg/ml周后，血浆中仍可测到邻氯烷。本品脂溶性高，主要储存于脂肪中。从尿中排出的水溶性代谢物约占给药量的25%。
【适应证】无法手术的、功能性和非功能性肾上腺皮质癌、肾上腺皮质增生以及肿瘤所致的皮质醇增多症。
【剂量】对於18岁以下的儿童，此药的疗效及安全性尚未完全确定，医生会视乎患者的体重或身体表面面积来决定每日服用的剂量
成人每日剂量為1至6克(可分3至4次服)，及后可逐步递增至每日8至10克。一般建议每日最高剂量為18克
【用药禁忌】对此药有过敏反应者不宜服用。
【用药注意】对於轻微至中等程度的肝臟或肾臟受损的患者，剂量可能需要根据药物的血液浓度相应下调；对於严重程度的肝臟或肾臟受损的患者则不建议服用此药。
【常见副作用】抑制中枢神经系统、眩晕、嗜睡、皮肤出疹、食慾不振、噁心、呕吐、腹泻等其他副作用：头痛、高血压、体位性低血压、抑鬱、神志不清、肌肉震颤、出血性膀胱炎等药物相互作用：
1. Spironolactone (螺内酯)可降低此药的疗效，故不建议同时使用
2. 酒精、第一代抗组织胺药物(sedative antihistamine)、镇静安眠药、吗啡类止痛药、抗癲癇症药等具中枢神经系统抑制的作用，合併使用可增加相关的副作用如嗜睡、眩晕等
3. 此药可增加肝臟对某些药物(如部份抗癲癇症药物、巴比妥类药物、Warfarin华法林等)的代谢，合併使用可使后者的药效下降，故需特别监察
4. 服药者在使用其他药物前请先徵询医生或药剂师的意见病患者及家属注意事项：
a. 此药乃化疗药物，在处理及弃置药物时须小心谨慎
b. 接触药物时最好配戴可弃置的手套，避免由孕妇处理药物
c. 饱肚服用此药可增加吸收
d. 此药可抑制中枢神经系统，引致嗜睡、眩晕等，故在服药期间儘量避免驾驶或操作机械等需要高度精神集中力的活动
e.服药期间可能出视肾上腺皮质功能不全 (adrenocortical insufficiency)，需要时医医生会為个别病人处方适当剂量的皮质激素作补充
f. 服药者如出现感染、创伤或其他疾病，应立即找医生诊治，以避免出现急性肾上腺皮质功能不全
【贮法】密闭、干燥，于阴凉处保存。

【原产地英文商品名】LYSODREN 500mg/tab 30tabs/bottle
【原产地英文药品名】MITOTANE
【中文参考商品译名】
注：以下产品不同规格和不同价格，购买时请以电话咨询为准！
·LYSODREN 500毫克/片 30片/瓶
·LYSODREN 500毫克/片 10片/瓶
【中文参考药品译名】米托坦
【生产厂家中文参考译名】百时美施贵宝
【生产厂家英文名】BRISTOL MYERS SQUIBB

Lysodren®
(mitotane tablets, USP)

Warnings Lysodren (mitotane tablets, USP) should be administered under the supervision of a qualified physician experienced in the uses of cancer chemotherapeutic agents. Lysodren should be temporarily discontinued immediately following shock or severe trauma since adrenal suppression is its prime action. Exogenous steroids should be administered in such circumstances, since the depressed adrenal may not immediately start to secrete steroids.

Lysodren Description
Lysodren® (mitotane tablets, USP) is an oral chemotherapeutic agent. It is best known by its trivial name, o,p′-DDD, and is chemically, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane. The chemical structure is shown below:

Lysodren is a white granular solid composed of clear colorless crystals. It is tasteless and has a slight pleasant aromatic odor. It is soluble in ethanol, isooctane, and carbon tetrachloride. It has a molecular weight of 320.05.

Inactive ingredients in Lysodren tablets are: avicel, Polyethylene Glycol 3350, silicon dioxide, and starch.

Lysodren is available as 500 mg scored tablets for oral administration.

Lysodren - Clinical Pharmacology

Lysodren can best be described as an adrenal cytotoxic agent, although it can cause adrenal inhibition, apparently without cellular destruction. Its biochemical mechanism of action is unknown. Data are available to suggest that the drug modifies the peripheral metabolism of steroids as well as directly suppressing the adrenal cortex. The administration of Lysodren alters the extra-adrenal metabolism of cortisol in man; leading to a reduction in measurable 17-hydroxy corticosteroids, even though plasma levels of corticosteroids do not fall. The drug apparently causes increased formation of 6-β-hydroxycortisol.

Data in adrenal carcinoma patients indicate that about 40% of oral Lysodren is absorbed and approximately 10% of the administered dose is recovered in the urine as a water-soluble metabolite. A variable amount of metabolite (1%-17%) is excreted in the bile and the balance is apparently stored in the tissues.

Following discontinuation of Lysodren, the plasma terminal half-life has ranged from 18 to 159 days. In most patients blood levels become undetectable after 6 to 9 weeks. Autopsy data have provided evidence that Lysodren is found in most tissues of the body; however, fat tissues are the primary site of storage. Lysodren is converted to a water-soluble metabolite.

No unchanged Lysodren has been found in urine or bile.

Indications and Usage for Lysodren

Lysodren is indicated in the treatment of inoperable adrenal cortical carcinoma of both functional and nonfunctional types.

Contraindications

Lysodren (mitotane tablets, USP) should not be given to individuals who have demonstrated a previous hypersensitivity to it.

Warnings

Lysodren should be temporarily discontinued immediately following shock or severe trauma, since adrenal suppression is its prime action. Exogenous steroids should be administered in such circumstances, since the depressed adrenal may not immediately start to secrete steroids.

Lysodren should be administered with care to patients with liver disease other than metastatic lesions from the adrenal cortex, since the metabolism of Lysodren may be interfered with and the drug may accumulate.

All possible tumor tissues should be surgically removed from large metastatic masses before Lysodren administration is instituted. This is necessary to minimize the possibility of infarction and hemorrhage in the tumor due to a rapid cytotoxic effect of the drug.

Long-term continuous administration of high doses of Lysodren may lead to brain damage and impairment of function. Behavioral and neurological assessments should be made at regular intervals when continuous Lysodren treatment exceeds 2 years.

A substantial percentage of the patients treated show signs of adrenal insufficiency. It therefore appears necessary to watch for and institute steroid replacement in those patients. However, some investigators have recommended that steroid replacement therapy be administered concomitantly with Lysodren. It has been shown that the metabolism of exogenous steroids is modified and consequently somewhat higher doses than normal replacement therapy may be required.

Precautions

General

Adrenal insufficiency may develop in patients treated with Lysodren, and adrenal steroid replacement should be considered for these patients.

Since sedation, lethargy, vertigo, and other CNS side effects can occur, ambulatory patients should be cautioned about driving, operating machinery, and other hazardous pursuits requiring mental and physical alertness.

Drug Interactions

Lysodren has been reported to accelerate the metabolism of warfarin by the mechanism of hepatic microsomal enzyme induction, leading to an increase in dosage requirements for warfarin. Therefore, physicians should closely monitor patients for a change in anticoagulant dosage requirements when administering Lysodren to patients on coumarin-type anticoagulants. In addition, Lysodren should be given with caution to patients receiving other drugs susceptible to the influence of hepatic enzyme induction.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic and mutagenic potentials of Lysodren (mitotane tablets, USP) are unknown. However, the mechanism of action of this compound suggests that it probably has less carcinogenic potential than other cytotoxic chemotherapeutic drugs.

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Lysodren. It is also not known whether Lysodren can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lysodren should be given to a pregnant woman only if clearly needed.

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 adverse reactions in nursing infants from mitotane, 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

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Lysodren did not include sufficient numbers of patients aged 65 years and older 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, 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.

Adverse Reactions

A very high percentage of patients treated with Lysodren have shown at least one type of side effect. The main types of adverse reactions consist of the following:

1. Gastrointestinal disturbances, which consist of anorexia, nausea or vomiting, and in some cases diarrhea, occur in about 80% of the patients.
2. Central nervous system side effects occur in 40% of the patients. These consist primarily of depression as manifested by lethargy and somnolence (25%), and dizziness or vertigo (15%).
3. Skin toxicity has been observed in about 15% of the cases. These skin changes consist primarily of transient skin rashes which do not seem to be dose related. In some instances, this side effect subsided while the patients were maintained on the drug without a change of dose. Infrequently occurring side effects involve the eye (visual blurring, diplopia, lens opacity, toxic retinopathy); the genitourinary system (hematuria, hemorrhagic cystitis, and albuminuria); cardiovascular system (hypertension, orthostatic hypotension, and flushing); and some miscellaneous effects including generalized aching, hyperpyrexia, and lowered protein bound iodine (PBI).

Overdosage

No proven antidotes have been established for Lysodren overdosage.

Lysodren Dosage and Administration

The recommended treatment schedule is to start the patient at 2 g to 6 g of Lysodren per day in divided doses, either 3 or 4 times a day. Doses are usually increased incrementally to 9 g to 10 g per day. If severe side effects appear, the dose should be reduced until the maximum tolerated dose is achieved. If the patient can tolerate higher doses and improved clinical response appears possible, the dose should be increased until adverse reactions interfere. Experience has shown that the maximum tolerated dose (MTD) will vary from 2 g to 16 g per day, but has usually been 9 g to 10 g per day. The highest doses used in the studies to date were 18 g to 19 g per day.

Treatment should be instituted in the hospital until a stable dosage regimen is achieved.

Treatment should be continued as long as clinical benefits are observed. Maintenance of clinical status or slowing of growth of metastatic lesions can be considered clinical benefits if they can clearly be shown to have occurred.

If no clinical benefits are observed after 3 months at the maximum tolerated dose, the case would generally be considered a clinical failure. However, 10% of the patients who showed a measurable response required more than 3 months at the MTD. Early diagnosis and prompt institution of treatment improve the probability of a positive clinical response. Clinical effectiveness can be shown by reduction in tumor mass; reduction in pain, weakness or anorexia; and reduction of symptoms and signs due to excessive steroid production.

A number of patients have been treated intermittently with treatment being restarted when severe symptoms have reappeared. Patients often do not respond after the third or fourth such course. Experience accumulated to date suggests that continuous treatment with the maximum possible dosage of Lysodren is the best approach.

Procedures for proper handling and disposal of anticancer drugs should be considered. 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 Lysodren tablets. Lysodren tablets should not be crushed. Personnel should avoid exposure to crushed and/or broken tablets. If contact with broken tablets occurs, wash immediately and thoroughly. More information is available in the references listed below.

How is Lysodren Supplied

Lysodren® (mitotane tablets, USP)

NDC 0015-3080-60—500 mg Tablets, bottle of 100

STORAGE

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].

REFERENCES

1. 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.
2. 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
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
4. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd ed.) Pittsburgh, PA: Oncology Nursing Society.

Manufactured for:
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
Made in Italy

1050972A4
Rev June 2010

----------------------------------------------
REPRESENTATIVE PACKAGING

See How Supplied section for a complete list of available packages of Lysodren.

NDC 0015-3080-60
100 TABLETS
Lysodren® (mitotane tablets, USP)
EACH TABLET CONTAINS 500 mg
Rx only
Bristol-Myers Squibb

一、药物知识：
Mitotane (米托坦)
【药理】本品可使肾上腺皮质萎缩和坏死。给予本品后可使体内肾上腺皮质激素及其代谢产物水平迅速下降，可用于肾上腺瘤或肾上腺增生引起的枯氏综合征。口服约40%由胃肠道吸收，其余60%以原型随粪便排出。每日5～10g，血药浓度可达10～90μg/ml，代谢物浓度30～50。停药6～9μg/ml周后，血浆中仍可测到邻氯烷。本品脂溶性高，主要储存于脂肪中。从尿中排出的水溶性代谢物约占给药量的25%。
【适应证】无法手术的、功能性和非功能性肾上腺皮质癌、肾上腺皮质增生以及肿瘤所致的皮质醇增多症。
二、世界医疗机构对Mitotane (米托坦)的临床研究结果：
意大利的8家医疗中心和47家德国医疗中心对实行根治性手术的177例肾上腺皮质癌患者进行为期20年的对照研究。其中47例意大利患者在根治术后接受辅助性米托坦治疗(米托坦组)，55例意大利患者(对照组1)和75例德国患者(对照组2)术后未经过辅助性米托坦治疗。米托坦组和对照组1中的患者基本情况相似;对照组2中的患者年龄明显较米托坦组和对照组1中的患者大。且I、II期患者较米托坦组多。术后对米托坦组随访56个月，对照组I随访67个月，对照组2随访43个月。
与对照组1(中位无复发生存期为10个月)和对照组2(中位无复发生存期为25个月)相比，米托坦组(中位无复发生存期为42个月)患者无复发生存期显著延长。米托坦组中位总生存期为110个月，与对照组1(52个月)相比延长58个月，与对照组2(67个月)相比延长43个月，可见辅助性米托坦治疗能显著延长肾上腺皮质癌患者无复发生存期，患者总生存期也有改善。米托坦相关不良反应主要是1、2级不良反应，但接受高剂量米托坦治疗的患者中，15%的息者观察到3级胃肠道不良事件，20%的患者观察到3级神经性不良事件。13%的患者需要暂时性药物减量。