温馨提醒：本说明书仅供参考，最新的说明书详见药品附带的说明书。

完整处方信息

警告：发生严重或严重创伤时的肾上腺危机

在服用LYSODREN的患者中，休克或严重外伤时会发生肾上腺危机，对休克的反应也会减弱。施用氢化可的松，监测电击迹象的升级，并终止赖索伦直至恢复[参见剂量和用法（2.2）和警告和注意事项（5.1） ]。

1适应症和用途

LYSODREN适用于治疗无法手术的，功能性或非功能性肾上腺皮质癌患者。

2用法用量

2.1推荐剂量

LYSODREN的推荐初始剂量为口服2 g至6 g，每天分三或四次。逐渐增加剂量以达到14至20 mg / L的血液浓度，或达到允许的浓度。

LYSODREN是一种细胞毒性药物。请遵循适用的特殊处理和处置程序。

2.2剂量修改

休克或严重创伤时的肾上腺危机

终止赖索伦直至恢复[参见警告和注意事项（5.1） ]。

中枢神经系统（CNS）毒性

终止赖索伦直至症状消失。症状缓解后七至十天，以较低的剂量重新开始（例如，减少500-1000 mg）[见警告和注意事项（5.2） ]。

3剂型和强度

500毫克白色，圆形，双凸刻痕片，在一侧一分为二，在另一侧的“ L1”上留下“ BL”。

4禁忌症

没有。

5警告和注意事项

5.1休克或严重创伤时的肾上腺危机

在服用LYSODREN的患者中，休克或严重外伤时会发生肾上腺危机，对休克的反应也会减弱。给予氢化可的松，监测休克的症状，并终止赖索伦直至恢复[见剂量和用法（2.2） ]。

5.2中枢神经系统毒性

LYSODREN治疗会产生中枢神经系统毒性，包括镇静，嗜睡和眩晕。线粒体血浆浓度超过20 mcg / mL会增加毒性反应。

5.3肾上腺功能不全

LYSODREN治疗可能导致肾上腺功能不全。根据临床指示进行类固醇替代治疗。测量游离皮质醇和促肾上腺皮质激素（ACTH）的水平，以实现最佳的类固醇替代。

5.4胚胎-胎儿毒性

LYSODREN对孕妇使用会造成胎儿伤害。怀孕期间暴露于米诺坦的患者可能会发生异常的妊娠结局，例如早产和早孕流产。建议孕妇注意胎儿的潜在危险。繁殖潜力的指教女性治疗过程中使用有效的避孕用LYSODREN和停药只要后米托坦血浆水平是可检测的[见特殊人群中使用（8.1，  8.3） ]。

5.5绝经前妇女的卵巢大囊肿

接受LYSODREN治疗的绝经前患者有卵巢大囊肿，通常为双侧或多发。已经报道了这些囊肿的并发症，包括附件扭转和出血性囊肿破裂。在某些情况下，已经描述了米线烷停药后的改善。如果女性患者出现妇科症状，例如阴道流血和/或骨盆疼痛，建议他们就医[见不良反应（6）]。

6不良反应

标签的其他部分详细讨论了以下不良反应：

•休克或严重创伤时的肾上腺危机[请参阅警告和注意事项（5.1） ]

•中枢神经系统毒性[ 请参阅警告和注意事项（5.2） ]

•肾上腺功能不全[ 请参阅警告和注意事项（5.3） ]
•卵巢大囊肿[请参阅警告和注意事项（5.5） ]

在临床试验或上市后报告中发现了与使用来索伦相关的下列不良反应。由于这些反应是从不确定大小的人群中自愿报告的，因此并非总是能够可靠地估计其发生频率或建立与药物暴露的因果关系。

LYSODREN治疗常见的不良反应包括：

•厌食，恶心，呕吐和腹泻（80％）

•抑郁，头晕或眩晕（15％-40％）

•皮疹（15％）•中性粒细胞减少症•生长迟缓，甲状腺功能减退

•精神错乱，头痛，共济失调，精神障碍，无力，构音障碍

•黄斑病•肝炎，肝酶升高•男性乳房发育症

•高胆固醇血症，高甘油三酸酯血症

•女性的血液雄烯二酮减少，血液睾丸激素减少，男性和女性的性激素结合球蛋白增加，男性的无血睾丸激素减少。

较不常见的不良反应包括：视力模糊，复视，晶状体混浊，视网膜病变，出血时间延长，血尿，出血性膀胱炎，蛋白尿，高血压，体位性低血压，潮红，全身酸痛和发烧。

7药物相互作用

7.1 CYP3A4底物

Mitotane是细胞色素P450 3A4（CYP3A4）的强诱导剂。当将LYSODREN给予接受CYP3A4底物药物的患者时，应监测患者对伴随药物的剂量要求的变化。

7.2华法林

向接受LYSODREN的患者服用香豆素类抗凝剂时，应监测凝血试验并根据需要调整抗凝剂量。

8在特定人群中的使用

8.1怀孕

风险摘要

LYSODREN可能造成胎儿伤害。有限的售后案例报告了在妊娠期间接受LYSODREN治疗的妇女的早产和早孕流产。尚未使用米诺坦进行动物繁殖研究。建议孕妇注意胎儿的潜在危险。对于所指示的人群，主要出生缺陷和流产的背景风险尚不清楚。在美国普通人群中，临床公认的怀孕中主要先天缺陷和流产的估计背景风险分别为2-4％和15-20％。

8.2哺乳

风险摘要

线粒体通过人乳排出。但是，尚不清楚LYSODREN对母乳喂养婴儿的影响或对产奶的影响。由于母乳喂养的婴儿可能会出现严重的不良反应，因此建议哺乳妇女不要在LYSODREN治疗期间和中断治疗后（只要可以检测到米诺坦血浆水平）不建议母乳喂养。

8.3生殖潜力的男性和女性

避孕

女性

当将LYSODREN施用于孕妇时，可能会造成胎儿伤害[见在特定人群中使用（8.1） ]。 劝告有生殖潜能的女性患者在LYSODREN治疗期间和中止治疗后，只要可检测到米诺坦血浆水平，即可使用有效的避孕方法[见临床药理学（12.3） ]。

8.4小儿使用

儿科患者的安全性和有效性尚未确定。

8.5老年人使用

LYSODREN的临床研究未包括足够多的65岁及以上的患者来确定他们是否与年轻患者有所不同。其他报告的临床经验尚未发现老年患者和年轻患者在反应方面的差异。一般而言，老年患者的剂量选择应谨慎，通常从给药范围的低端开始，这反映出肝，肾或心脏功能下降以及伴随疾病或其他药物治疗的频率更高。

8.6肝功能不全

肝功能损害可能会干扰线粒体的代谢，药物可能会积聚。对肝功能不全的患者慎用LYSODREN。

11说明

LYSODREN（米托坦）是一种口服的肾上腺细胞毒性剂。化学名称是（±）-1,1-二氯-2-（邻氯苯基）-2-（对氯苯基）乙烷（也称为邻，p'-DDD）。化学结构为：

线粒体是由透明无色晶体组成的白色颗粒状固体。无味，有轻微的芳香气味。它可溶于乙醇，分子量为320.05。

LYSODREN中的非活性成分是：微晶纤维素，聚乙二醇3350，二氧化硅和淀粉。

12临床药理学

12.1行动机制

米托坦是一种肾上腺细胞毒性剂，其作用机理未知。线粒体修饰类固醇的外周代谢并直接抑制肾上腺皮质。据报道，在没有皮质类固醇浓度降低和6-β-羟基皮质醇形成增加的情况下，17-羟基皮质类固醇的减少。

12.2药效学

线粒体的药效学是未知的。

12.3药代动力学

吸收性

LYSODREN口服后，40％的剂量被吸收。

分配

在人体的大多数组织中都发现了线粒体。但是，脂肪是分配的主要场所。

消除

终止米线烷后，血浆终末半衰期为18到159天（中位数为53天）。

代谢

线粒体转化为水溶性代谢产物。

排泄

在尿液或胆汁中未发现不变的米诺坦。尿液中约有10％的剂量以水溶性代谢物的形式回收。胆汁中排出了数量不等的代谢物（1％-17％）。

13毒理学

13.1致癌，诱变，生育力受损

线粒体的致癌性和致突变性未知。

15参考

1.OSHA。http://www.osha.gov/SLTC/hazardousdrugs/index.html

16供应/存储和处理方式

LYSODREN片剂以500毫克白色，圆形，双凸，刻痕片剂的形式提供，在一侧一分为二，在另一侧的“ L1”上留下“ BL”字样。

每瓶100片：NDC 76336-080-60

将瓶子存放在25°C（77°F）；允许在15°C至30°C（59°F-86°F）之间的偏移。

线粒体是一种细胞毒性药物。请遵循适用的特殊处理和处置程序[请参阅参考文献（15） ]。

17患者咨询信息

肾上腺危机

•建议患者在休克或严重外伤时停用LYSODREN，并立即与他们的医疗保健提供者联系。•建议患者将任何计划的手术告知其医疗保健提供者。

卵巢大囊肿

•劝告绝经前妇女如果遇到妇科症状，例如阴道流血和/或骨盆疼痛，请就医[ 见警告和注意事项（5.5） ]。

胚胎-胎儿毒性

•告知女性可能对胎儿造成潜在危险的生殖潜能，并告知其保健提供者已知或疑似怀孕[见警告和注意事项（5.4）和在特定人群中的使用（8.1） ]。

•劝告有生殖潜力的女性在治疗期间和中止治疗后，在其医疗保健提供者的指导下使用有效的避孕方法（请参见“ 在特定人群中使用（8.3） ”）。

哺乳期

•劝告那些在用LYSODREN治疗期间不要哺乳的女性[见特殊人群的使用（8.2） ]。

致电以下医疗查询：
Direct Success Inc.
1710 Hwy 34
Farmingdale，NJ 07727
844-597-6373
844 Lysodren
传真：（855）674-6767

制造商：
Corden Pharma Latina SpA
Via del Murillo Km。2.800
04013 Sermoneta（拉丁）
意大利

对于：法国HRA医药稀有疾病

主要显示面板-100片瓶装纸箱

NDC 76336-080-60

LYSODREN
（米托坦）片剂，口服使用

每片含
500毫克

仅100 Tablets Rx

HRA药物罕见疾病

温馨提醒：本说明书仅供参考，最新的说明书详见药品附带的说明书。

本说明书来源于FDA网站

https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/f0cd76e9-460c-450e-b094-172e636f340a/spl-doc?hl=Mitotane

温馨提醒：

①建议您用 谷歌浏览器  在电脑上或手机  打开以上链接，就可以自动翻译成简体中文，而且翻译的还比较准确。

②本说明书仅供参考，最新的说明书详见药品附带的说明书

FULL PRESCRIBING INFORMATION

WARNING: ADRENAL CRISIS IN THE SETTING OF SHOCK OR SEVERE TRAUMA

In patients taking LYSODREN, adrenal crisis occurs in the setting of shock or severe trauma and response to shock is impaired. Administer hydrocortisone, monitor for escalating signs of shock and discontinue LYSODREN until recovery [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

LYSODREN is indicated for the treatment of patients with inoperable, functional or nonfunctional, adrenal cortical carcinoma.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The recommended initial dose of LYSODREN is 2 g to 6 g orally, in three or four divided doses per day. Increase doses incrementally to achieve a blood concentration of 14 to 20 mg/L, or as tolerated.

LYSODREN is a cytotoxic drug. Follow applicable special handling and disposal procedures.

2.2 Dose Modifications

Adrenal Crisis in the Setting of Shock or Severe Trauma

Discontinue LYSODREN until recovery [see Warnings and Precautions (5.1)].

Central Nervous System (CNS) Toxicity

Discontinue LYSODREN until symptoms resolve. Seven to 10 days after symptoms resolve, restart at a lower dose (for example, decrease by 500-1000 mg) [see Warnings and Precautions (5.2)].

3 DOSAGE FORMS AND STRENGTHS

500 mg white, round, biconvex, scored tablets, bisected on one side and impressed with "BL" over "L1" on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Adrenal Crisis in the Setting of Shock or Severe Trauma

In patients taking LYSODREN, adrenal crisis occurs in the setting of shock or severe trauma and response to shock is impaired. Administer hydrocortisone, monitor for escalating signs of shock, and discontinue LYSODREN until recovery [see Dosage and Administration (2.2)].

5.2 CNS Toxicity

CNS toxicity, including sedation, lethargy, and vertigo, occurs with LYSODREN treatment. Mitotane plasma concentrations exceeding 20 mcg/mL are associated with a greater incidence of toxicity.

5.3 Adrenal Insufficiency

Treatment with LYSODREN can cause adrenal insufficiency. Institute steroid replacement as clinically indicated. Measure free cortisol and corticotropin (ACTH) levels to achieve optimal steroid replacement.

5.4 Embryo-Fetal Toxicity

LYSODREN can cause fetal harm when administered to a pregnant woman. Abnormal pregnancy outcomes, such as preterm births and early pregnancy loss, can occur in patients exposed to mitotane during pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LYSODREN and after discontinuation of treatment for as long as mitotane plasma levels are detectable [see Use in Specific Populations (8.1, 8.3)].

5.5 Ovarian Macrocysts in Premenopausal Women

Ovarian macrocysts, often bilateral and multiple, have been reported in premenopausal patients receiving LYSODREN. Complications from these cysts, including adnexal torsion and hemorrhagic cyst rupture, have been reported. In some cases, improvement after mitotane discontinuation has been described. Advise female patients to seek medical care if they experience gynecological symptoms such as vaginal bleeding and/or pelvic pain [seeAdverse Reactions (6)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

•  Adrenal Crisis in the Setting of Shock or Severe Trauma [see Warnings and Precautions (5.1)]

•   CNS Toxicity [seeWarnings and Precautions (5.2)]

•   Adrenal Insufficiency [seeWarnings and Precautions (5.3)]
•   Ovarian macrocysts [seeWarnings and Precautions (5.5)]

The following adverse reactions associated with the use of LYSODREN were identified in clinical trials or postmarketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

Common adverse reactions occurring with LYSODREN treatment include:

•Anorexia, nausea, vomiting, and diarrhea (80%)

•Depression, dizziness, or vertigo (15%-40%)

•Rash (15%)•Neutropenia•Growth retardation, hypothyroidism

•Confusion, headache, ataxia, mental impairment, weakness, dysarthria

•Maculopathy•Hepatitis, elevation of liver enzymes•Gynecomastia

•   Hypercholesterolemia, hypertriglyceridemia

• Decreased blood androstenedione and decreased blood testosterone in females, increased sex hormone binding globulin in females      and males, decreased blood free testosterone in males.

Less common adverse reactions include: visual blurring, diplopia, lens opacity, retinopathy, prolonged bleeding time, hematuria, hemorrhagic cystitis, albuminuria, hypertension, orthostatic hypotension, flushing, generalized aching, and fever.

7 DRUG INTERACTIONS

7.1 CYP3A4 Substrates

Mitotane is a strong inducer of cytochrome P450 3A4 (CYP3A4). Monitor patients for a change in dosage requirements for the concomitant drug when administering LYSODREN to patients receiving drugs that are substrates of CYP3A4.

7.2 Warfarin

When administering coumarin-type anticoagulants to patients receiving LYSODREN, monitor coagulation tests and adjust the anticoagulant dose as needed.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

LYSODREN can cause fetal harm. Limited postmarketing cases report preterm births and early pregnancy loss in women treated with LYSODREN during pregnancy. Animal reproduction studies have not been conducted with mitotane. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary

Mitotane is excreted in human milk; however, the effect of LYSODREN on the breastfed infant, or effect on milk production is unknown. Because of the potential for serious adverse reactions in the breastfed infant, advise nursing women that breastfeeding is not recommended during treatment with LYSODREN and after discontinuation of treatment for as long as mitotane plasma levels are detectable.

8.3 Females and Males of Reproductive Potential

Contraception

Females

LYSODREN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with LYSODREN and after discontinuation of therapy for as long as mitotane plasma levels are detectable [see Clinical Pharmacology (12.3)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 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 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 Hepatic Impairment

Hepatic impairment may interfere with the metabolism of mitotane and the drug may accumulate. Administer LYSODREN with caution to patients with hepatic impairment.

11 DESCRIPTION

LYSODREN (mitotane) is an oral adrenal cytotoxic agent. The chemical name is (±)-1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane (also known as o,p′-DDD). The chemical structure is:

Mitotane 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 and has a molecular weight of 320.05.

Inactive ingredients in LYSODREN are: microcrystalline cellulose, polyethylene glycol 3350, silicon dioxide, and starch.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mitotane is an adrenal cytotoxic agent with an unknown mechanism of action. Mitotane modifies the peripheral metabolism of steroids and directly suppresses the adrenal cortex. A reduction in 17-hydroxycorticosteroids in the absence of decreased corticosteroid concentrations and increased formation of 6-β-hydroxycortisol have been reported.

12.2 Pharmacodynamics

The pharmacodynamics of mitotane are unknown.

12.3 Pharmacokinetics

Absorption

Following oral administration of LYSODREN, 40% of the dose is absorbed.

Distribution

Mitotane is found in most tissues of the body; however, fat is the primary site of distribution.

Elimination

Following discontinuation of mitotane, the plasma terminal half-life ranges from 18 to 159 days (median 53 days).

Metabolism

Mitotane is converted to a water-soluble metabolite.

Excretion

No unchanged mitotane is found in urine or bile. 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenicity and mutagenicity of mitotane are unknown.

15 REFERENCES

1.OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 HOW SUPPLIED/STORAGE AND HANDLING

LYSODREN tablets are supplied as 500 mg white, round, biconvex, scored tablets, bisected on one side and impressed with "BL" over "L1" on the other side.

100 tablets per bottle: NDC 76336-080-60

Store bottles at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F-86°F).

Mitotane is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)].

17 PATIENT COUNSELING INFORMATION

Adrenal Crisis

•Advise patients to discontinue LYSODREN in the case of shock or severe trauma and contact their healthcare provider immediately.

•Advise patients to tell their healthcare provider of any planned surgeries.

Ovarian Macrocysts

• Advise premenopausal women to seek medical care if they experience gynecological symptoms such as vaginal bleeding and/or pelvic pain [see Warnings and Precautions(5.5)].

Embryo-Fetal Toxicity

•Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].

•Advise females of reproductive potential to use effective contraception during treatment and after discontinuation of treatment for as long as instructed by their healthcare provider [see Use in Specific Populations (8.3)].

Lactation

•Advise females who are nursing not to breastfeed during treatment with LYSODREN [see Use in Specific Populations (8.2)].

Address medical inquiries to:
Direct Success Inc.
1710 Hwy 34
Farmingdale, NJ 07727
844-597-6373
844 Lysodren
Fax: (855) 674-6767

Manufactured by:
Corden Pharma Latina S.p.A.
Via del Murillo Km. 2.800
04013 Sermoneta (Latina)
Italy

For : HRA Pharma Rare Diseases, France

PRINCIPAL DISPLAY PANEL - 100 Tablet Bottle Carton

NDC 76336-080-60

LYSODREN
(mitotane) tablets, for oral use

EACH TABLET CONTAINS
500 mg

100 Tablets
Rx only

HRA Pharma Rare Diseases

【备注】以上内容仅供参考，不作为用药依据，详情请参照药品附带说明书。