商標名
Opeprim
一般名
ミトタン（mitotane）（JAN）
化学名
1,1‐Dichloro‐2‐(2‐chlorophenyl)‐2‐(4‐chlorophenyl）ethane
構造式

分子式
C14H10Cl4
分子量
320.04
融　点
75～79℃
性　状
白色～微黄白色の結晶で、わずかに特異なにおいがあり、味はない。クロロホルム、四塩化炭素、アセトニトリル又はシクロヘキサンに溶けやすく、エタノール（95）又はイソオクタンにやや溶けやすく、水にほとんど溶けない。
組成
１カプセル中：ミトタン含量
500mg
１カプセル中：添加物
カプセル内容物：セラセフェート、ステアリン酸Mg、タルク
１カプセル中：添加物
カプセル本体：ラウリル硫酸Na、ゼラチン
効能又は効果
効能又は効果／用法及び用量
副腎癌
手術適応とならないクッシング症候群
用法及び用量
通常成人１回１カプセル～２カプセル１日３回経口投与から開始し、有効量まで漸増し、以後、症状、血中・尿中ステロイド濃度、副作用等により適宜増減する。
薬効薬理
1. 細胞毒作用6)
副腎組織の変化は皮質に選択的であり、とくに皮質の束状層、網状層の萎縮や壊死がイヌにおいて認められている。
2. ステロイド合成阻害作用7)～12)
ステロイド分泌量の低下が認められるが、その合成阻害部位は、まだ決定されていない。種々の実験による推定阻害部位は、次の反応段階である。
コレステロール側鎖切断の段階
副腎癌及びクッシング病患者各６例、イヌ（in vitro)
３位脱水素の段階
副腎癌及びクッシング病患者各６例、ウシ（in vitro)
21位水酸化の段階
副腎癌患者３例
11位水酸化の段階
副腎癌患者３例、ウシ(in vitro)

18位水酸化の段階
ヒトの摘出副腎癌
3. ステロイド代謝への作用（外国人データ)13)
コルチゾールの代謝物のうち、６β‐ヒドロキシ体を増加させる。
包装
100カプセル（バラ）

製造販売元
株式会社ヤクルト本社
原资料附件：http://www.info.pmda.go.jp/go/pack/2499006M1026_2_05/

雙氯苯二氯乙烷（米托坦）
英文名稱：
Mitotane
性狀：
本品與殺蟲劑DDT同屬一類化合物，能選擇性地作用於腎上腺皮質細胞，對正常腎上腺皮質細胞或瘤細胞均有損傷作用。對碳鏈裂解?系、11-β羥化?和2l-羥化?有較強抑制作用，對皮質激素生物合成的多個環節起抑制作用，它還能誘導肝細胞合成參與甾類激素代謝的某些?類，加速甾體分解。用藥後可使腎上腺皮質激素及其代謝產物在尿中和血中的濃度迅速降低。臨床用於治療腎上腺皮質癌或皮質功能亢進而誘發的庫欣綜合征。
作用與作用機制：
口服從胃腸道吸收約40％，5-15g/d時，血中原形藥物濃度為7-90μg/ml，代謝產物為29-54μg/ml。停藥後6-9周仍能在血中測出，體內分布廣泛，但主要貯存在脂肪組織。給藥量中10％-25％以水溶性代謝產物的形式由尿中排出，其餘由膽汁中排出。
藥動學：
極大多數患者有惡心、嘔吐、腹瀉；約40％有中樞反應，如嗜睡、共濟失調、眩暈和精神抑制；眼的不良反應有視覺模糊、復視、晶狀體混濁和視網膜病變；其他不良反應有過敏反應、蛋白尿、皮疹、發熱、出血性膀胱炎、色素沈著、高血壓和體位性低血壓。治療期間可能出現皮質功能減退，在創傷和休克時應暫時停藥，並給予皮質激素。
臨床應用：
口服：開始時2-6g/d，分3-4次服，然後調整到最大耐受量2-16g/d。
用法計量：
片劑：0.5g。
Generic Name: mitotane
Dosage Form: tablet
Lysodren®
(mitotane tablets, USP)
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:
Gastrointestinal disturbances, which consist of anorexia, nausea or vomiting, and in some cases diarrhea, occur in about 80% of the patients.
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%).
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。
STORAGE
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].