【中文品名】磷酸雌莫司汀钠
【通用药名】ESTRAMUSTINE PHOSPHATE SODIUM Estramustine
【别　　名】磷雌氮芥钠，Emcyt, Estracyt, KES-504, Ro-21-8837

【用　　途】为甾类烷基化物抗肿瘤药，用于治疗前列腺癌。主要副作用为恶心和呕吐，其它包括男子女性型乳房、血栓性静脉炎、肺栓塞、中风心肌梗塞和充血性心力衰竭。 

药品详细说明 

雌莫司汀副作用;别名:雌莫司汀磷酸钠、癌腺治、雌氮芥磷酸二钠、雌氮芥磷酸钠、雌二醇氮芥磷酸钠、雌莫司汀磷酸二钠、磷雌醇氮芥钠、Emecyt、 Estracyt、EstramustinePhosphateSodium、EstramustineDisodiumPhosphate;雌莫司汀适 应症:主要用

于晚期前列腺癌，特别是对常规激素治疗无效的患者。此外对胰腺癌亦有一定的疗效。;雌莫司汀药理学作用:磷酸雌二醇氮芥为烷化剂(正氮芥)与 激素(雌二醇-17-β-磷酸盐)通过氨基甲酸酯连接组成。该药进入体内后迅速脱磷酸，形成具有细胞毒活性的代谢物雌二醇氮芥(E2M)，进而氧化成雌酮 氮芥(E1M)，发挥细胞毒性作用。E2M和E1M与前列腺癌细胞中雌二醇结合蛋白(EMBP)有高度亲和力，能被前列腺癌组织大量摄取。研究表明E2M 与E1M细胞毒作用为抑制前列腺细胞有丝分裂，裂解已形成的微管并阻止其再形成。E2M还促使前列腺癌细胞中谷胱甘肽的排空，增加其抗有丝分裂作用。另 外，该药还有微弱的雌激素作用和明显抗促性腺激素作用，减少睾酮的产生和分泌。本药为细胞毒抗癌药，以雌二醇17磷酸酯为载体，具有烷化剂及雌激素的双重 作用，可通过类固醇受体特异性地把药物导入前列腺组织，产生细胞毒效能和激素效果，达到破坏癌细胞的目的。由于药物对肿瘤作用的专一性，从而提高了疗效， 并减轻了烷化剂的全身反应。药物的细胞毒效能包括：阻止前列腺癌细胞的有丝分裂；裂解已形成的微管并阻止微管的再形成；对前列腺癌的细胞核蛋白质起作用； 促使前列腺癌细胞中谷胱甘肽的排空。本药治疗剂量时对骨髓的抑制极少或无影响，对未经治疗的以及已经用过常规激素治疗失败的患者同样有效。由于其严重不良 反应的发生率低，可用于长期治疗。 

药物剂型 
1.胶囊：140mg；2.注射剂(粉)：150mg，300mg，每盒有10瓶ETM及10注射稀释液。 
药理作用 
磷酸雌二醇氮芥为烷化剂(正氮芥)与激素(雌二醇-17-β-磷酸盐)通过氨基甲酸酯连接组成。该药进入体内后迅速脱磷酸，形成具有细 胞毒活性的代谢物雌二醇氮芥(E2M)，进而氧化成雌酮氮芥(E1M)，发挥细胞毒性作用。E2M和E1M与前列腺癌细胞中雌二醇结合蛋白(EMBP)有 高度亲和力，能被前列腺癌组织大量摄取。研究表明E2M与E1M细胞毒作用为抑制前列腺细胞有丝分裂，裂解已形成的微管并阻止其再形成。E2M还促使前列 腺癌细胞中谷胱甘肽的排空，增加其抗有丝分裂作用。另外，该药还有微弱的雌激素作用和明显抗促性腺激素作用，减少睾酮的产生和分泌。本药为细胞毒抗癌药， 以雌二醇17磷酸酯为载体，具有烷化剂及雌激素的双重作用，可通过类固醇受体特异性地把药物导入前列腺组织，产生细胞毒效能和激素效果，达到破坏癌细胞的 目的。由于药物对肿瘤作用的专一性，从而提高了疗效，并减轻了烷化剂的全身反应。药物的细胞毒效能包括：阻止前列腺癌细胞的有丝分裂；裂解已形成的微管并 阻止微管的再形成；对前列

腺癌的细胞核蛋白质起作用；促使前列腺癌细胞中谷胱甘肽的排空。本药治疗剂量时对骨髓的抑制极少或无影响，对未经治疗的以及已经 用过常规激素治疗失败的患者同样有效。由于其严重不良反应的发生率低，可用于长期治疗。 
药动学 
口服吸收良好，吸收率约为75%，药物浓集于前列腺组织中。用药后，迅速脱磷氧基形成雌二醇氮芥，其大部分被氧化为雌酮氮芥。口服时， 脱磷氧基作用在胃肠道进行。活性代谢物有些蓄积在身体的脂肪组织内，其消除是经过进一步代谢，其产物大部分从胆道排泄，少量从肾脏排泄。雌酮氮芥的血浆半 衰期是10～12h。该药有10%～15%代谢成雌激素。 
适应证 
主要用于晚期前列腺癌，特别是对常规激素治疗无效的患者。此外对胰腺癌亦有一定的疗效。 
禁忌证 
1.对雌二醇或氮芥类药物过敏；
2.严重肝脏或心脏疾病；
3.活动性血栓性静脉炎或血栓栓塞性疾病。 
注意事项 
慎用：
1.水钠潴留。
2.糖尿病。
3.高血压。
4.消化性溃疡。
5.脑血管疾病。
6.冠心病。 
不良反应 

1.常见短暂恶心，偶有呕吐，腹泻罕见。
2.少数人出现白细胞、血小板减少及肝功能异常，可见血清氨基转移酶和胆红素升高，一旦减量或停药，可以完全恢复。
3.少数人出现过敏性皮疹、水肿及咽痛。
4.同雌激素治疗一样，可出现血栓栓塞性疾病、男性乳房增大、性功能减退。 

用法用量 
1.口服给药：每天2次，每次200～300mg，若连服3～4周后仍无效，则应停药。如病情好转，应按原剂量继续服用3～4个月。药物剂量应根据疗程、疗效和不良反应等进行适当调整。
2.静脉注射：可用于治疗开始时，每天300mg，共用3周后改为口服，每次200～300mg，每天2次，或继续静脉注射，每周两次，每次300mg。 
药物相应作用 
1.与含钙药物(如含钙的抗酸剂) 或与牛奶、奶制品同服，本药的血药浓度降低。
2.与活疫苗同用，有增加被活疫苗感染的风险。但处于缓解期的白血病患者，可以在化疗停止后至少间隔3个月再接种活疫苗。
3.与牛奶、奶制品或其他含钙食物同服，本药血药浓度降低。
4.注射剂配制时不能用盐水，将8ml稀释液缓缓注入药瓶中，不能振荡，以防产生泡沫。

Natco Estramustine Capsules Details:

Brand Name: X-Trant
Contents: Estramustine phosphate
Form: Capsule
Manufacturer: Natco Pharma Ltd
Strength:140 mg
Packing: Pack of 100 Capsules

Emcyt®
(estramustine phosphate sodium) Capsules

Estramustine phosphate sodium, an antineoplastic agent, is an off-white powder readily soluble in water. EMCYT Capsules are white and opaque, each containing estramustine phosphate sodium as the disodium salt monohydrate equivalent to 140 mg estramustine phosphate, for oral administration. Each capsule also contains magnesium stearate, silicon dioxide, sodium lauryl sulfate, and talc. Gelatin capsule shells contain the following pigment: titanium dioxide.

Chemically, estramustine phosphate sodium is estra-1,3,5(10)-triene-3,17-diol(17β)-,3-[bis(2- chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate. It is also referred to as estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate. Estramustine phosphate sodium has an empiric formula of C23H30Cl2NNa2O6P•H2O, a calculated molecular weight of 582.4, and the following structural formula:

Indications & Dosage

EMCYT Capsules are indicated in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate.

The recommended daily dose is 14 mg per kg of body weight (ie, one 140 mg capsule for each 10 kg or 22 lb of body weight), given in 3 or 4 divided doses. Most patients in studies in the United States have been treated at a dosage range of 10 to 16 mg per kg per day.

Patients should be instructed to take EMCYT Capsules at least 1 hour before or 2 hours after meals. EMCYT should be swallowed with water. Milk, milk products, and calcium-rich foods or drugs (such as calcium-containing antacids) must not be taken simultaneously with EMCYT.

Patients should be treated for 30 to 90 days before the physician determines the possible benefits of continued therapy. Therapy should be continued as long as the favorable response lasts. Some patients have been maintained on therapy for more than 3 years at doses ranging from 10 to 16 mg per kg of body weight per day.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

White opaque capsules, each containing estramustine phosphate sodium as the disodium salt monohydrate equivalent to 140 mg estramustine phosphate—bottle of 100 (NDC 0013-0132-02).

NOTE

EMCYT Capsules should be stored in the refrigerator at 36° to 46°F (2° to 8°C).

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83–2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC, 20402.

2. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics, JAMA. 1985; 253 (11):1590–1592.

3. National Study Commission on Cytotoxic Exposure-Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

4. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia. 1983; 1:426–428.

5. Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians. 1983; (Sept/Oct) 258–263.

6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033–1049.

7. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. Am J Hosp Pharm. 1986; 43:1193–1204.

8. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32–41.

Distributed by: pfizer, pharmacia&Upjohn Company, Division of pfizer Inc, NY 10017. Revised: June 2007

Side Effects & Drug Interactions

In a randomized, double-blind trial comparing therapy with EMCYT Capsules in 93 patients (11.5 to 15.9 mg/kg/day) or diethylstilbestrol (DES) in 93 patients (3.0 mg/day), the following adverse effects were reported:

Milk, milk products, and calcium-rich foods or drugs may impair the absorption of EMCYT.

Warnings

It has been shown that there is an increased risk of thrombosis, including fatal and nonfatal myocardial infarction, in men receiving estrogens for prostatic cancer. EMCYT Capsules should be used with caution in patients with a history of thrombophlebitis, thrombosis, or thromboembolic disorders, especially if they were associated with estrogen therapy. Caution should also be used in patients with cerebral vascular or coronary artery disease.

Because glucose tolerance may be decreased, diabetic patients should be carefully observed while receiving EMCYT.

Because hypertension may occur, blood pressure should be monitored periodically.

Precautions

Fluid Retention. Exacerbation of preexisting or incipient peripheral edema or congestive heart disease has been seen in some patients receiving therapy with EMCYT Capsules. Other conditions which might be influenced by fluid retention, such as epilepsy, migraine, or renal dysfunction, require careful observation.

EMCYT may be poorly metabolized in patients with impaired liver function and should be administered with caution in such patients.

Because EMCYT may influence the metabolism of calcium and phosphorus, it should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia or in patients with renal insufficiency. Patients with prostate cancer and osteoblastic metastases are at risk for hypocalcemia and should have calcium levels closely monitored.

Gynecomastia and impotence are known estrogenic effects.

Allergic reactions and angioedema at times involving the airway have been reported.

Certain endocrine and liver function tests may be affected by estrogen-containing drugs. EMCYT may depress testosterone levels. Abnormalities of hepatic enzymes and of bilirubin have occurred in patients receiving EMCYT. Such tests should be done at appropriate intervals during therapy and repeated after the drug has been withdrawn for two months.

Long-term continuous administration of estrogens in certain animal species increases the frequency of carcinomas of the breast and liver. Compounds structurally similar to EMCYT are carcinogenic in mice. Carcinogenic studies of EMCYT have not been conducted in man. Although testing by the Ames method failed to demonstrate mutagenicity for estramustine phosphate sodium, it is known that both estradiol and nitrogen mustard are mutagenic. For this reason and because some patients who had been impotent while on estrogen therapy have regained potency while taking EMCYT, the patient should be advised to use contraceptive measures.

Overdosage & Contraindications

Although there has been no experience with overdosage to date, it is reasonable to expect that such episodes may produce pronounced manifestations of the known adverse reactions. In the event of overdosage, the gastric contents should be evacuated by gastric lavage and symptomatic therapy should be initiated. Hematologic and hepatic parameters should be monitored for at least 6 weeks after overdosage of EMCYT Capsules.

EMCYT Capsules should not be used in patients with any of the following conditions:

1. Known hypersensitivity to either estradiol or to nitrogen mustard.

2. Active thrombophlebitis or thromboembolic disorders, except in those cases where the actual tumor mass is the cause of the thromboembolic phenomenon and the physician feels the benefits of therapy may outweigh the risks.

Clinical Pharmacology

Estramustine phosphate (Figure 1) is a molecule combining estradiol and nornitrogen mustard by a carbamate link. The molecule is phosphorylated to make it water soluble.

Estramustine phosphate taken orally is readily dephosphorylated during absorption, and the major metabolites in plasma are estramustine (Figure 2), the estrone analog (Figure 3), estradiol, and estrone.

Prolonged treatment with estramustine phosphate produces elevated total plasma concentrations of estradiol that fall within ranges similar to the elevated estradiol levels found in prostatic cancer patients given conventional estradiol therapy. Estrogenic effects, as demonstrated by changes in circulating levels of steroids and pituitary hormones, are similar in patients treated with either estramustine phosphate or conventional estradiol.

The metabolic urinary patterns of the estradiol moiety of estramustine phosphate and estradiol itself are very similar, although the metabolites derived from estramustine phosphate are excreted at a slower rate.