Generic Name: Estramustine Phosphate Sodium
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate)-estra-1,3,5(10)-triene-3,17-diol (17β) disodium salt
Molecular Formula: C23H30Cl2NNa2O6P
CAS Number: 2998-57-4
Introduction
Antimicrotubule antineoplastic agent; a complex of 17 β-estradiol and nornitrogen mustard.1 2 3 9 13 15
Uses for Emcyt
Prostate Cancer
Palliative treatment of metastatic and/or progressive prostate cancer.1 13
Considered by many clinicians to be an alternative to conventional measures (e.g., orchiectomy, hormonal therapy); generally used in treatment of hormone-refractory prostate cancer.2 4 5 14 15
Combination therapy with etoposide, paclitaxel, or vinblastine9 may result in higher objective response rates and greater improvements in subjective parameters (e.g., pain) for treatment of hormone-refractory disease.2 9
Emcyt Dosage and Administration
General
Consult specialized references for procedures for proper handling and disposal of antineoplastics.
Administration
Oral Administration
Administer orally 3 or 4 times daily.1 13
Food or calcium-containing products may decrease absorption.1 2 13 Administer orally 1 hour before or 2 hours after meals with water; avoid concomitant administration with calcium-containing foods or beverages (e.g., milk, milk products) or drugs (e.g., calcium-containing antacids).1 2 13
Dosage
Available as estramustine phosphate sodium; dosage expressed in terms of estramustine phosphate.1
Adults
Prostate Cancer
Oral
14 mg/kg (i.e., one 140-mg capsule for each 10 kg or 22 lb of body weight) daily in 3 or 4 divided doses.1 13 In clinical studies in the US, most patients received dosages of 10–16 mg/kg daily.1 13
Administer 30–90 days before assessing potential benefits of continuing.1 13 Continue therapy as long as response is satisfactory; some patients have received >3 years.1
Cautions for Emcyt
Contraindications
Known hypersensitivity to estramustine, estradiol (or other estrogens), nitrogen mustard, or any ingredient in the formulation.1 15
Active thrombophlebitis or thromboembolic disorders, except when such conditions are caused by the tumor mass, and clinician judges that anticipated benefits outweigh potential risks.1
Warnings/Precautions
Warnings
Estrogenic Effects
Risk of adverse effects from estrogenic metabolites; consider cautions, precautions, and contraindications associated with estrogens.15
Risk of breast tenderness1 and mild or moderate breast enlargement.1 Gynecomastia1 2 3 4 7 10 13 and impotence1 are known estrogenic effects.1
Cardiovascular Effects
Risk of thrombotic and thromboembolic disorders,13 including thrombophlebitis,1 3 AMI,1 11 pulmonary embolism,1 10 13 cerebrovascular accident,1 11 and leg cramps.1 Use with caution in patients with history of thrombophlebitis, thrombosis, or thromboembolic disorders (especially if associated with estrogen use); caution in patients with cerebrovascular or coronary artery disease.1
Hypertension4 may occur; monitor BP periodically.1
Endocrine and Metabolic Effects
Risk of decreased glucose tolerance;4 15 patients with diabetes mellitus should be carefully monitored.1
Sensitivity Reactions
Risk of angioedema, rash, and pruritus.1
Major Toxicities
Cardiovascular Effects
Risk of exacerbation of preexisting or incipient peripheral edema1 3 4 8 9 or CHF.1 3 Use with caution in patients with conditions that might be aggravated by fluid retention (e.g., CHF, epilepsy, migraine, renal dysfunction), and carefully monitor such patients.1 13
Hepatic Effects
Risk of elevated AST (SGOT), LDH,15 and/or bilirubin concentrations.2 15 Monitor liver function during and for 2 months following discontinuance.1
GI Effects
Risk of nausea,1 2 3 4 6 7 8 9 10 13 diarrhea,1 3 4 8 13 and minor GI upset.1
General Precautions
Fetal/Neonatal Morbidity and Mortality
Estramustine was not mutagenic in the Ames test; however, estradiol and nitrogen mustard are known mutagens.1 Avoid pregnancy during therapy.1
Metabolic Effects
Potential influence on metabolism of calcium and phosphorus; use with caution in patients with metabolic bone diseases associated with hypercalcemia or in patients with renal impairment.1 Risk of hypocalcemia in patients with prostate cancer and osteoblastic metastases; closely monitor calcium concentrations.a
Specific Populations
Pregnancy
Category X.15 (See Fetal/Neonatal Morbidity and Mortality under Cautions.) Not intended for use in women.15
Lactation
Not intended for use in women.15
Pediatric Use
Safety and efficacy not established; use not recommended in pediatric patients.15
Geriatric Use
Safety and efficacy not specifically studied to date.15 Careful monitoring for toxicity recommended.15
Hepatic Impairment
Decreased metabolism in patients with hepatic impairment; use with caution.1
Renal Impairment
May influence metabolism of calcium and phosphorus; use with caution.1
Common Adverse Effects
Nausea, diarrhea, minor GI upset, breast tenderness, breast enlargement, edema, elevated AST [SGOT] and/or LDH concentrations, dyspnea.1
Interactions for Emcyt
Calcium-containing Foods or Drugs
Potential decreased absorption when administered concomitantly with calcium-containing foods or beverages (e.g., milk, milk products) or drugs (e.g., calcium-containing antacids).1 3 13 (See Oral Administration under Dosage and Administration.)
Emcyt Pharmacokinetics
Absorption
Bioavailability
After oral administration, approximately 75% of estramustine phosphate absorbed into GI tract tissues and rapidly dephosphorylated to cytotoxic estramustine, most of which is subsequently oxidized to an active cytotoxic metabolite, estromustine.1 2 3 9 13 Relative bioavailability of estromustine is approximately 44%.2
Peak plasma concentrations of estromustine usually are attained within 2–4 hours.2 3 Estramustine phosphate not detected in plasma after oral administration.2 3 b
Food
Calcium-containing foods or beverages (e.g., milk, milk products) may decrease absorption.1
Distribution
Extent
Estramustine and estromustine are distributed into prostatic carcinoma tissues and plasma; the tumor to plasma concentration ratio of estramustine or estromustine is approximately 6 or 1, respectively.3
Elimination
Metabolism
Approximately 10–20% of estramustine or estromustine is metabolized to estradiol or estrone, respectively.2 3 9 13 Markedly elevated estradiol concentrations detected as early as 1 week of estramustine phosphate initiation; may persist for 7–12 weeks after discontinuance.15
Elimination Route
Estramustine, estromustine, and their metabolites excreted principally in bile; <1% of conjugated estradiol and estrone excreted in urine.1 3 13 15
Half-life
After oral administration, mean elimination half-life of estromustine was approximately 10.3 hours.3
Special Populations
Decreased metabolism in patients with hepatic impairment.1
Stability
Storage
Oral
Capsules
2–8° C.1
ActionsActions
Estramustine and estromustine bind to tubulin and/or microtubule-associated proteins,2 3 9 13 15 resulting in depolymerization of microtubules and, subsequently, cellular metaphase arrest.2 3 13
May damage cell membrane, promote DNA breakage, interfere with DNA replication, and induce cellular apoptosis in other cell lines (e.g., glioma cells, colon cancer cells).2 3 15
Advice to Patients
Importance of using effective contraception method during therapy; if pregnancy occurs in the partner of a patient, advise patient and partner of risk to the fetus.1
Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Capsules | 140 mg (of estramustine phosphate) | Emcyt | Pfizer |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Emcyt 140MG Capsules (PFIZER U.S.): 150/$892 or 450/$2584.99
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 01, 2004. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
1. Pharmacia. Emcyt (estramustine phosphate sodium) capsules prescribing information. Kalamazoo, MI; 1999 Feb.
2. Perry CM, McTavish D. Estramustine phosphate sodium: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer. Drugs Aging. 1995; 7:49-74. [PubMed 7579781]
3. Bergenheim AT and Henriksson R. Pharmacokinetics and pharmacodynamics of estramustine phosphate. Clin Pharmacokinet. 1998; 34:163-72. [PubMed 9515186]
4. Anon. Drug of choice for cancer chemotherapy. Med Lett Drugs Ther. 2000; 42:83-92. [PubMed 10994034]
5. Prostate cancer. From: PDQ Information for Health Care Professionals (database). Bethesda, MD: National Cancer Institute; 2002 Feb. From NCI website.
6. Benson RC, Wear JB, and Gill GM. Treatment of stage D hormone- resistant carcinoma of the prostate with estramustine phosphate. J Urol. 1979; 121:452-4. [IDIS 122742] [PubMed 439216]
7. Mittelman A, Shukla SK, and Murphy GP. Extended therapy of stage D carcinoma of the prostate with oral estramustine phosphate. J Urol. 1976; 115:409-12. [PubMed 1263317]
8. de Kernion JN, Murphy GP, Priore R et al. Comparison of flutamide and Emcyt in hormone- refractory metastatic prostatic cancer. Urology. 1988; 31:312-7. [PubMed 3281365]
9. Hudes G, Einhorn L, Ross E et al. Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: a Hoosier Oncology Group and Fox Chase Network phase III trial. J Clin Oncol. 1999; 17:3160-6. [IDIS 436791] [PubMed 10506613]
10. Kuhn MW, Weissbach L, and Hinke A for the Prostate Cancer Study Group. Primary therapy of metastatic prostate carcinoma with depot gonadotropin-releasing hormone analogue goserelin versus estramustine phosphate. Urology. 1994; 43(Suppl 2):61-7. [PubMed 8116135]
11. Johansson JE, Andersson SO, Beckman KW et al. Clinical evaluation of flutamide and estramustine as initial treatment of metastatic carcinoma of prostate. Urology. 1987; 29:55-9. [PubMed 3798631]
12. Roessler W, Hinke A, and Wieland WF. Experience in advanced prostatic cancer: orchiectomy and flutamide versus orchiectomy and estramustine phosphate. Urology. 1994; 43(Suppl 2):57-60. [PubMed 8116134]
13. Rowinsky EK and Tolcher AW. Antimicrotubule agents. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:431- 52.
14. Carroll PR, Lee KL, Fuks ZY et al. Cancer of the prostate. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:1418-79
15. Pharmacia, Kalamazoo, MI: Personal communication.
a. Pharmacia. Emcyt (estramustine phosphate sodium) capsules prescribing information. Kalamazoo, MI; 2003 Mar.
b. Hudes G, Haas N, Yeslow G et al. Phase I clinical and pharmacologic trial of intravenous estramustine phosphate. J Clin Oncol. 2002; 20:1115-27. [IDIS 479067] [PubMed 11844837]
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