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.^{1 2 3 9 13 15}

Uses for Estramustine

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}

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.^{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 Estramustine

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 Gynecomastia^{1 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 edema^{1 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

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).^{1 3 13} (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.^{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

Actions

• 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.

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

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