Estramustine Phosphate Sodium
C23H30ClNNaO6P
• Estramustine phosphate sodium, a complex of 17 ?-estradiol and nornitrogen mustard, is an antimicrotubule antineoplastic agent.
Uses
Estramustine phosphate sodium is used for the palliative treatment of metastatic and/or progressive prostate cancer. The drug, alone or in combination with other antineoplastic agents, currently is considered by many clinicians to be an alternative to conventional measures (e.g., orchiectomy, hormonal therapy) and generally is used in the treatment of hormone-refractory prostate cancer.
Safety and efficacy of estramustine have been evaluated in controlled and uncontrolled studies in patients with advanced metastatic prostate cancer refractory to conventional measures (e.g., hormonal therapy) as well as in those with previously untreated disease. Most studies were conducted before the realization that administration of estramustine with milk or calcium-containing products substantially impairs absorption of the drug; therefore, overall clinical efficacy (i.e., objective response) of estramustine may have been underestimated. Efficacy of estramustine has been determined based on objective (e.g., National Prostate Cancer Project [NPCP] criteria, prostate specific antigen [PSA] concentrations) and/or subjective (e.g., World Health Organization [WHO] criteria, Eastern Cooperative Oncology Group [ECOG] criteria) response rates; effects on survival have not been clearly elucidated.
Estramustine exhibits limited activity when used as monotherapy in patients with advanced metastatic prostate cancer refractory to conventional measures (e.g., hormonal therapy). In these patients, monotherapy with estramustine (560-840 mg orally daily in 3 divided doses) for at least 3 weeks resulted in objective response rates of 19-69%; no complete responses were observed. A mean objective response rate of 37% was reported in an analysis of 634 patients with hormone-refractory prostate cancer who received oral estramustine therapy in several clinical trials. In patients with hormone-refractory disease, estramustine appears to be more effective in producing objective responses than streptozocin, as effective as epirubicin or flutamide, and less effective than medroxyprogesterone; estramustine appears to be as effective as mitomycin in the management of progressive disease. Combination therapy consisting of estramustine plus etoposide, paclitaxel, or vinblastine appears to be associated with higher objective response rates and greater improvements in subjective parameters (e.g., pain) compared with those achieved with estramustine monotherapy.
In patients with previously untreated advanced prostate cancer, monotherapy with estramustine resulted in objective response rates of 73-96%. Estramustine appears to be at least as effective as estrogen therapy, flutamide, or goserelin in such patients.
Dosage and Administration
• General
Estramustine phosphate sodium should be used under the supervision of a qualified clinician experienced in the treatment of prostate cancer. The manufacturer recommends that procedures for proper handling and disposal of antineoplastic agents, including estramustine phosphate, be considered. (See the ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs at http://www.ahfsdruginformation.com.)
Estramustine phosphate sodium is administered orally 3 or 4 times daily. Because food may reduce GI absorption of estramustine phosphate sodium, the drug should be given 1 hour before or 2 hours after meals. Estramustine phosphate sodium should be taken with water; the drug should not be taken concurrently with calcium-containing foods or beverages (e.g., milk, milk products) or drugs (e.g., calcium-containing antacids) since absorption may be substantially reduced.
Dosage of estramustine phosphate sodium is expressed in terms of estramustine phosphate. The recommended dosage of estramustine phosphate for the palliative treatment of metastatic and/or progressive prostate cancer is 14 mg/kg (i.e., one 140-mg capsule for each 10 kg of body weight) daily in 3 or 4 divided doses. In clinical studies in the US, most patients received a daily dosage of 10-16 mg/kg.
Patients should be treated with estramustine phosphate for 30-90 days before assessing the potential benefits of continued therapy. Therapy should be continued as long as a satisfactory response is maintained; some patients have been maintained on estramustine phosphate therapy (at dosages of 10-16 mg/kg daily) for more than 3 years.
• Special Populations
No special population dosage recommendations at this time.
Cautions
• Contraindications
Estramustine phosphate sodium is contraindicated in patients with known hypersensitivity to estramustine, estradiol (or other estrogens), nitrogen mustard, or any ingredient in the formulation. 1, 15 The drug also is contraindicated in patients with active thrombophlebitis or thromboembolic disorders, except in those cases in which the actual tumor mass is the cause of the thromboembolic phenomenon and, in the judgment of the clinician, anticipated benefits of estramustine therapy outweigh the potential risks.
• Warnings/Precautions
Warnings
The estrogenic metabolites of estramustine (e.g., estradiol, estrone) share the toxic potentials of other estrogens, and the usual cautions, precautions, and contraindications associated with estrogen therapy should be observed.
Cardiovascular Effects Thrombotic and thromboembolic disorders, including thrombophlebitis, myocardial infarction, pulmonary embolism, and cerebrovascular accident, have been reported in 2-3% of patients receiving estramustine in clinical studies. Leg cramps have been reported in 8% of patients who received estramustine in clinical studies. The incidence of adverse cardiovascular events appears to be similar among patients receiving estramustine and in those receiving estrogen (i.e., diethylstilbestrol) therapy. 2, 15 The manufacturer states that estramustine should be used with caution in patients with a history of thrombophlebitis, thrombosis, or thromboembolic disorders, especially those associated with estrogen therapy. The drug also should be used with caution in patients with cerebrovascular or coronary artery disease.
Because hypertension may occur, the manufacturer states that blood pressure should be monitored periodically during estramustine therapy.
Endocrine and Metabolic Effects Decreased glucose tolerance has occurred in patients receiving estrogen therapy and may occur in patients receiving estramustine . The manufacturer states that patients with diabetes mellitus shouldbe carefully monitored during estramustine therapy.
Sensitivity Reactions
Sensitivity reactions, including angioedema, have been reported during therapy with estramustine. Rash or pruritus reportedly occurred in 1 or 2%, respectively, of patients receiving the drug in clinical studies.
Major Toxicities
Cardiovascular Effects Exacerbation of preexisting or incipient peripheral edema or congestive heart disease has been reported in some patients receiving estramustine. Edema or congestive heart failure occurred in 19 or 3%, respectively, of patients receiving the drug in clinical studies. Estramustine should be used with caution in patients with conditions that might be aggravated by fluid retention (e.g., congestive heart failure, epilepsy, migraine, renal dysfunction), and such patients should be carefully monitored during therapy with the drug.
Hepatic Effects Elevated AST (SGOT) and/or LDH concentrations occurred in approximately 31% and elevated bilirubin concentrations occurred in approximately 1% of patients receiving estramustine in clinical studies. Liver function tests should be performed at appropriate intervals during and for 2 months following discontinuance of estramustine therapy. (See Specific Populations: Hepatic Impairment.)
Endocrine and Genitourinary Effects Breast tenderness was reported in approximately 66% of patients receiving estramustine in clinical studies. Mild or moderate breast enlargement was reported in 60 or 10%, respectively, of patients receiving estramustine in clinical studies. Gynecomastia and impotence are known estrogenic effects.
GI Effects Nausea, diarrhea, or minor GI upset occurred in 15, 12, or 11%, respectively, of patients receiving estramustine in clinical studies. Anorexia or flatulence occurred in 4 or 2%, respectively, of patients receiving estramustine in clinical studies, while vomiting, GI bleeding, burning throat, or thirst each occurred in 1% of patients.
General Precautions
Fetal/Neonatal Morbidity and Mortality Although estramustine was not mutagenic in the Ames test, estradiol and nitrogen mustard are known to be mutagenic. There are no adequate and well-controlled studies to date in humans. However, because of the mutagenic potential of estramustine, patients should be advised to use an effective method of contraception during therapy with the drug.
Metabolic Effects Because estramustine may influence the metabolism of calcium and phosphorus, the drug should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia or in patients with renal insufficiency.
Specific Populations
Pregnancy Category X. (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: General Precautions, in Cautions.) (See Users Guide) Not intended for use in women.
Lactation Not intended for use in women.
Pediatric Use Safety and efficacy not established in pediatric patients; use not recommended in these patients.
Geriatric Use Safety and efficacy in geriatric patients have not been specifically studied to date. However, estramustine has been evaluated extensively in the treatment of prostate cancer, which occurs principally in patients older than 50 years of age. Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturer states that patients in this age group should be monitored closely while receiving estramustine therapy.
Renal Impairment Estramustine may influence the metabolism of calcium and phosphorus; use with caution in patients with renal impairment.
Hepatic Impairment Decreased metabolism in patients with hepatic impairment; use with caution in such patients.
• Common Adverse Effects
The most common adverse effects associated with estramustine are those related to the drug’s estrogen metabolites and include GI, endocrine, cardiovascular, and hepatic effects. 1, 15 (See Cautions: Warnings/Precautions.) Other adverse effects occurring in 1% or more of patients receiving estramustine in clinical studies include dyspnea, lethargy, leukopenia, easy bruising, insomnia, dry skin, emotional lability, upper respiratory discharge, hoarseness, headache, anxiety, chest pain, thrombocytopenia, flushing, thinning hair, peeling skin at fingertip, and tearing of eyes.
Drug Interactions
• Calcium-containing Foods or Drugs
Potential pharmacokinetic interaction (decreased absorption) when estramustine is used concomitantly with calcium-containing foods or beverages (e.g., milk, milk products) or drugs (e.g., calcium-containing antacids).
• Description
Estramustine phosphate sodium, a complex of 17 ?-estradiol and nornitrogen mustard linked together by a carbamate ester bridge, is an antimicrotubule antineoplastic agent. While the exact mechanisms of action are complex and have not been fully elucidated, the beneficial effects of estramustine in the palliative treatment of prostate cancer generally are believed to result from the drug’s cytotoxic and antigonadotropic activities.
Following oral administration, estramustine phosphate sodium is rapidly dephosphorylated in the GI tract to estramustine, most of which is subsequently oxidized to an active cytotoxic metabolite, estromustine. Estramustine and estromustine exert their cytotoxic effects principally by binding to tubulin and/or microtubule-associated proteins. Binding of estramustine or estromustine to these protein subunits induces depolymerization of microtubules, resulting in cellular metaphase arrest. The antimicrotubule effects of estramustine appear to be related principally to the intact estramustine or estromustine complex; only a minor cytotoxic effect has been associated with the nornitrogen mustard moiety. Limited data indicate that the drug also may damage the cell membrane, promote DNA breakage, interfere with DNA replication, and induce cellular apoptosis in other cell lines (e.g., glioma cells, colon cancer cells).
Approximately 10-20% of estramustine or estromustine is metabolized to estradiol or estrone, respectively. Markedly elevated estradiol concentrations have been detected as early as 1 week following initiation of estramustine therapy and may persist for 7-12 weeks following discontinuance of the drug. Estradiol and estrone exert antigonadotropic effects and have been shown to decrease plasma concentrations of testosterone, dihydrotestosterone, gonadotropins, cholesterol, and 17-hydroxyprogesterone; estradiol and estrone also may increase prolactin and cortisol concentrations. Because total plasma concentrations of estradiol during prolonged therapy with estramustine increase to levels similar to those achieved with conventional estradiol therapy, estrogenic effects may be similar in patients receiving estramustine and in those receiving oral estradiol. Some data indicate that reductions in testosterone concentrations associated with estramustine therapy may be comparable to or greater than those achieved after surgical castration.
Estramustine and estromustine and their metabolites are excreted principally in bile; a small amount (less than 1%) of conjugated estradiol and estrone is excreted in urine.
• Advice to Patients
Necessity of advising patients to use an effective method of contraception while receiving therapy; if pregnancy occurs in the partner of a patient during therapy, advise patient and partner of risk to the fetus. Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant diseases.
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the manufacturer’s labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs at http://www.ahfsdruginformation.com.
Preparations
Estramustine Phosphate Sodium
Oral
Capsules 140 mg (of estramustine Emcyt®, phosphate) Pfizer
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