Estramustine (Monograph)

Brand name: Emcyt
Drug 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.

Uses for Estramustine

Prostate Cancer

Palliative treatment of metastatic and/or progressive prostate cancer.

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.

Combination therapy with etoposide, paclitaxel, or vinblastine may result in higher objective response rates and greater improvements in subjective parameters (e.g., pain) for treatment of hormone-refractory disease.

Estramustine 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.

Food or calcium-containing products may decrease absorption. 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).

Dosage

Available as estramustine phosphate sodium; dosage expressed in terms of estramustine phosphate.

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. In clinical studies in the US, most patients received dosages of 10–16 mg/kg daily.

Administer 30–90 days before assessing potential benefits of continuing. Continue therapy as long as response is satisfactory; some patients have received >3 years.

Cautions for Estramustine

Contraindications

Known hypersensitivity to estramustine, estradiol (or other estrogens), nitrogen mustard, or any ingredient in the formulation.
Active thrombophlebitis or thromboembolic disorders, except when such conditions are caused by the tumor mass, and clinician judges that anticipated benefits outweigh potential risks.

Warnings/Precautions

Warnings

Estrogenic Effects

Risk of adverse effects from estrogenic metabolites; consider cautions, precautions, and contraindications associated with estrogens.

Risk of breast tenderness and mild or moderate breast enlargement. Gynecomastia and impotence are known estrogenic effects.

Cardiovascular Effects

Risk of thrombotic and thromboembolic disorders, including thrombophlebitis, AMI, pulmonary embolism, cerebrovascular accident, and leg cramps. 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.

Hypertension may occur; monitor BP periodically.

Endocrine and Metabolic Effects

Risk of decreased glucose tolerance; patients with diabetes mellitus should be carefully monitored.

Sensitivity Reactions

Risk of angioedema, rash, and pruritus.

Major Toxicities

Cardiovascular Effects

Risk of exacerbation of preexisting or incipient peripheral edema or CHF. 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.

Hepatic Effects

Risk of elevated AST (SGOT), LDH, and/or bilirubin concentrations. Monitor liver function during and for 2 months following discontinuance.

GI Effects

Risk of nausea, diarrhea, and minor GI upset.

General Precautions

Fetal/Neonatal Morbidity and Mortality

Estramustine was not mutagenic in the Ames test; however, estradiol and nitrogen mustard are known mutagens. Avoid pregnancy during therapy.

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. Risk of hypocalcemia in patients with prostate cancer and osteoblastic metastases; closely monitor calcium concentrations.

Specific Populations

Pregnancy

Category X. (See Fetal/Neonatal Morbidity and Mortality under Cautions.) Not intended for use in women.

Lactation

Not intended for use in women.

Pediatric Use

Safety and efficacy not established; use not recommended in pediatric patients.

Geriatric Use

Safety and efficacy not specifically studied to date. Careful monitoring for toxicity recommended.

Hepatic Impairment

Decreased metabolism in patients with hepatic impairment; use with caution.

Renal Impairment

May influence metabolism of calcium and phosphorus; use with caution.

Common Adverse Effects

Nausea, diarrhea, minor GI upset, breast tenderness, breast enlargement, edema, elevated AST [SGOT] and/or LDH concentrations, dyspnea.

Drug Interactions

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). (See Oral Administration under Dosage and Administration.)

Estramustine 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. Relative bioavailability of estromustine is approximately 44%.

Peak plasma concentrations of estromustine usually are attained within 2–4 hours. Estramustine phosphate not detected in plasma after oral administration.

Food

Calcium-containing foods or beverages (e.g., milk, milk products) may decrease absorption.

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.

Elimination

Metabolism

Approximately 10–20% of estramustine or estromustine is metabolized to estradiol or estrone, respectively. Markedly elevated estradiol concentrations detected as early as 1 week of estramustine phosphate initiation; may persist for 7–12 weeks after discontinuance.

Elimination Route

Estramustine, estromustine, and their metabolites excreted principally in bile; <1% of conjugated estradiol and estrone excreted in urine.

Half-life

After oral administration, mean elimination half-life of estromustine was approximately 10.3 hours.

Special Populations

Decreased metabolism in patients with hepatic impairment.

Stability

Storage

Oral

Capsules

2–8° C.

Actions

Estramustine and estromustine bind to tubulin and/or microtubule-associated proteins, resulting in depolymerization of microtubules and, subsequently, cellular metaphase arrest.
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).

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.
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.
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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.