Professional Information
Estramustine (Systemic)
VA CLASSIFICATION
Primary: AN900
Commonly used brand name(s): Emcyt.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antineoplastic. —
Indications
Accepted
Carcinoma, prostatic (treatment)—Estramustine is indicated for palliative treatment of metastatic, progressive, and/or [ hormone-refractory]1 {08} {09} {10} {11} {12} {13} {14} {15} {16} {17} {18} {19} {20} {21} {22} (Evidence rating: IA) carcinoma of the prostate gland {01}.
1 Not included in Canadian product labeling.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
Estramustine phosphate sodium: 582.36 {05}
Mechanism of action/Effect:
Exact mechanism of antineoplastic action is unknown. Structurally, estramustine is a phosphorylated combination of estradiol and mechlorethamine (nitrogen mustard). However, estramustine has very weak alkylating activity and may be effective in some patients refractory to estrogen therapy. Therefore, its antineoplastic activity may be due to the estrogen component, a direct effect of estramustine or one of its metabolites, other antimitotic {02} activity, or a combination of effects. Prolonged use elevates total plasma estradiol concentrations to within ranges similar to those produced in prostatic carcinoma patients given conventional estradiol therapy {01}. Estrogenic effects (changes in circulating concentrations of steroids and pituitary hormones) are also similar to those produced by estradiol {01}. A suppressive effect on the hypothalamic-hypophyseal-gonadal axis with a resultant reduction in serum testosterone concentrations may also be involved. Estramustine is highly localized in prostatic tissue because of binding to an estramustine-specific protein {02}.
Absorption:
Well absorbed (up to 75%) from the gastrointestinal tract; impaired by milk, milk products, and other substances high in calcium {01}.
Biotransformation:
Rapidly dephosphorylated during absorption into peripheral circulation {01}, then estramustine is oxidized and hydrolyzed to estromustine, with low levels of estradiol and estrone, and to mechlorethamine; metabolism is by conjugation in the liver.
Half-life:
Multiphasic; 20 hours (terminal phase).
Elimination:
Biliary/fecal; renal (minor). The metabolites derived from estramustine phosphate are excreted at a slower rate than the native agent {05}.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients sensitive to estradiol or mechlorethamine may be sensitive to estramustine also {01}.
Carcinogenicity/Mutagenicity
Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.
Studies with estramustine have not been done {01}. Antimitotic agents have been associated with an increased risk of development of secondary carcinomas in humans. Long-term continuous administration of estrogens in some animals has been associated with an increased frequency of carcinomas of the breast and liver. Compounds structurally similar to estramustine are carcinogenic in mice {01}.
Although estramustine was not found to be mutagenic in Ames tests, both estradiol and nitrogen mustard alone are mutagenic.
Pregnancy/Reproduction
Fertility—
Gonadal suppression, resulting in azoospermia, has been reported in patients taking estramustine. These effects appear to be related to dose and length of therapy and may be irreversible. On the other hand, patients impotent from previous therapy may regain potency when taking estramustine.
Antimitotic agents have been reported to cause alterations in sperm cells that could result in mutagenicity and teratogenicity.
Pregnancy—
Because of the possibility of mutagenic effects, patients or their partners should be advised to use contraceptive measures {05}.
Geriatrics
Appropriate studies on the relationship of age to the effects of estramustine have not been performed in the geriatric population. However, elderly patients are more likely to have age-related renal function impairment and/or peripheral vascular disease, which may require caution in patients receiving estrogens.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Calcium-containing medications{01} or
Calcium supplements (calcium binds with estramustine in the gastrointestinal tract and forms an insoluble calcium phosphate salt, which is not absorbed; simultaneous administration should be avoided)
{01}
Corticosteroids, glucocorticoid (concurrent use with estrogens may alter the metabolism and protein binding of the glucocorticoids, leading to decreased clearance, increased elimination half-life, and increased therapeutic and toxic effects of the glucocorticoids; glucocorticoid dosage adjustment may be required during and following concurrent use)
Corticotropin (chronic therapeutic use) (concurrent use with estrogens may potentiate the anti-inflammatory effects of endogenous cortisol [adrenal secretion of endogenous cortisol is increased by corticotropin])
» Hepatotoxic medications (see Appendix II ) (concurrent use of these medications with estrogens may increase the risk of hepatotoxicity)
» Smoking, tobacco (not recommended during estrogen therapy because of the increased risk of serious cardiovascular side effects, including cerebrovascular accident, transient ischemic attacks, thrombophlebitis, and pulmonary embolism; risk increases with increasing tobacco usage and with age)
Vaccines, killed virus (because normal defense mechanisms may be suppressed by estramustine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)
Vaccines, live virus (because normal defense mechanisms may be suppressed by estramustine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the estramustine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With diagnostic test results
» Metyrapone test (reduced response)
Norepinephrine-induced platelet aggregability (may be increased)
Sulfobromophthalein (BSP) test (increased BSP retention)
Thyroid function test (protein-bound thyroxine [T 4] is increased; serum free T 4 concentrations may be unchanged or decreased; triiodothyronine [T 3] serum resin uptake is decreased, because estrogens increase serum thyroid-binding globulin [TBG]; serum T 3 may be increased)
With physiology/laboratory test values
Alanine aminotransferase (AST [SGOT]) values, and
Bilirubin concentrations, serum and
Lactate dehydrogenase (LDH) values (may be increased)
Antithrombin 3 concentrations and
Folate concentrations, serum and
Pregnanediol excretion and
Pyridoxine concentrations (may be decreased)
Ceruloplasmin and
Cortisol and
Glucose and
Phospholipids and
Prolactin and
Prothrombin and clotting factors VII, VIII, IX, and X and
Sodium and
Triglycerides (serum concentrations may be increased)
Phosphate (serum concentrations may be decreased {03})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Note: Estramustine may be poorly metabolized in patients with impaired liver function and should be administered with caution in such patients {05}. Estramustine also may influence the metabolism of calcium and phosphorus {05}. Therefore, it should be used with caution in patients who have metabolic bone diseases that are associated with hypercalcemia and in patients with renal insufficiency {05}.
Except under special circumstances, this medication should not be used when the following medical problems exist:
» Hypersensitivity to estramustine or
» Hypersensitivity to estradiol or
» Hypersensitivity to mechlorethamine (estramustine is a molecule combining estradiol and normechlorethamine by a carbamate link {05}. It should not be used if the patient is known to be hypersensitive to either estradiol or nitrogen mustard {05})
» Thromboembolic disorders, active, including recent myocardial infarction or stroke or
» Thrombophlebitis, active (may be aggravated by estrogen component; an exception may be made when the actual tumor mass is the cause of the thromboembolic phenomenon {01})
Risk-benefit should be considered when the following medical problems exist
Asthma or
Cardiac insufficiency or
Epilepsy or
Mental depression, or history of or
Migraine headaches or
Renal function impairment (fluid retention sometimes caused by estrogen component may aggravate these conditions)
Bone disease, metabolic, associated with hypercalcemia or
Renal insufficiency (estrogens influence metabolism of calcium and phosphorus {01})
Bone marrow depression, moderate to severe
Cerebrovascular disease or
Coronary artery disease or
» Thrombophlebitis, thrombosis, or thromboembolic disorders, history of, especially if associated with estrogen therapy{01} (risk of thromboembolic disorders caused by estrogens)
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster (risk of severe generalized disease)
Cholestatic jaundice, history of, including previous jaundice that occurred with estrogens or as a reaction to other medication
Diabetes mellitus (glucose tolerance may be decreased {01})
Gallbladder disease, or history of, especially gallstones
Hepatic function impairment (reduced metabolism and possible hepatotoxicity)
» Hypercalcemia associated with metastatic breast disease
» Peptic ulcer
Patient monitoring
The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition (» = major clinical significance):
Acid phosphatase values, serum and/or
Alkaline phosphatase values, serum (to assess response; elevated values should be reduced)
Blood counts, complete and
Platelet counts (may be appropriate at periodic intervals, although leukopenia and thrombocytopenia are rare with estramustine)
Blood pressure{01} and
Hepatic function (determinations recommended at periodic intervals)
Calcium concentrations, serum and
Phosphate concentrations, serum{03} (recommended at periodic intervals, especially in patients with bone metastases)
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Sodium and fluid retention (swelling of feet or lower legs)
Incidence rare
Allergic reaction (skin rash or fever)
anemia (unusual tiredness or weakness)
leukopenia (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—usually asymptomatic
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic
thrombosis (severe or sudden headaches; sudden loss of coordination; pains in chest, groin, or leg, especially calf of leg; sudden and unexplained shortness of breath; sudden slurred speech; sudden vision changes; weakness or numbness in arm or leg)
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Breast tenderness or enlargement —incidence 20 to 50%
decreased interest in sex{04} —occurs in most patients{04}
diarrhea —incidence 20 to 50%
nausea —incidence 20 to 50%
Incidence less frequent
Trouble in sleeping{01}
vomiting
Note: Vomiting is intolerable in approximately 8% of patients.
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
There has been no documented experience with estramustine overdose {05}. However, it is reasonable to expect that such episodes may produce pronounced manifestations of the known adverse reactions {05}.
Treatment of overdose
Treatment of overdose is symptomatic and supportive {01}.
To decrease absorption—Removal of gastric contents by gastric lavage.
Monitoring—Monitoring of hematologic and hepatic parameters for at least 6 weeks.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Estramustine (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to estramustine, estradiol, or mechlorethamine
Pregnancy—It is recommended that patients or their partners use contraceptive measures
Other medications, especially hepatotoxic medications
Other medical problems, especially chickenpox, herpes zoster, hypercalcemia, peptic ulcer, active or history of thromboembolic disorders (including recent myocardial infarction or stroke), or active or history of thrombophlebitis
Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed
For best results, taking 1 hour before or 2 hours after meals or milk or milk products {01}
» Frequently causes nausea and sometimes causes vomiting; checking with physician before discontinuing medication
Checking with physician if vomiting occurs shortly after dose is taken
» Proper dosing
Missed dose: Not taking at all; not doubling doses
» Proper storage
Precautions while using this medication
» Importance of close monitoring by physician
» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth
Side/adverse effects
Signs of potential side effects, especially sodium and fluid retention, allergic reaction, anemia, leukopenia, thrombocytopenia, and thrombosis
General Dosing Information
Patients receiving estramustine should be under supervision of a physician experienced in cancer chemotherapy.
Patients should be treated for 30 to 90 days before the physician determines the possible benefits of continued therapy {05}. Therapy should be continued as long as the response to estramustine is favorable {05}. 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 (mg/kg) per day {05}.
Nausea and vomiting sometimes responds to treatment with phenothiazines but may be severe enough to necessitate withdrawal of estramustine in some patients.
Diet/Nutrition
Patients should be instructed to take estramustine at least 1 hour before or 2 hours after meals {05}. Estramustine should be swallowed with water {05}. Milk, milk products, or calcium-rich foods or medications should not be taken simultaneously with estramustine {05}.
Oral Dosage Forms
ESTRAMUSTINE PHOSPHATE SODIUM CAPSULES
Usual adult dose
Carcinoma, prostatic
Oral, 600 mg (base) per square meter of body surface area per day in three divided doses (one hour before or two hours after meals) or 14 mg per kg of body weight (range 10 to 16 mg per kg) per day in three or four divided doses (one hour before or two hours after meals) {01}.
Strength(s) usually available
U.S.—
140 mg (base) (Rx) [Emcyt]
Canada—
140 mg (base) (Rx) [Emcyt]
Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), in a tight container, unless otherwise specified by the manufacturer. Protect from light.
Auxiliary labeling:
• Take 1 hour before or 2 hours after meals.
• Avoid milk or milk products.
Revised: 06/24/1998
References
Note: References used in the development and subsequent revisions of this monograph have not been incorporated into the database and therefore are not listed below.
- Emcyt package insert (Roche—US), Rev 4/84; (Pharmacia—US), Rev 2/87; Rev 6/87; Rev 11/87; (Kabi—US), Rev 5/93.
- Panel comment, 1988.
- Reviewer comment.
- Reviewer comment.
- Emcyt package insert (Roche—US), Rev 10/94, Rec 8/97.
- Hauser AR, Merryman R. Estramustine phosphate sodium. Drug Intell Clin Pharm 1984 May; 18: 368-74.
- Dorr RT, Fritz WL. Cancer chemotherapy handbook. New York: Elsevier; 1980. p. 406-9.
- Pienta KJ, Redman G, Bandekar R, et al. A phase II trial of oral estramustine and oral etoposide in hormone refractory prostate cancer. Urol 1997; 50(3): 401-6.
- Peinta KJ, Redman G, Hussain M, et al. Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. J Clin Oncol 1994; 12(10): 2005-12.
- Hudes GR, Nathan F, Khater C, et al. Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer. J Clin Oncol 1997; 15(9): 3156-63.
- Hudes GR, Greenberg R, Krigel RL, et al. Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. J Clin Oncol 1992; 10(11): 1754-61.
- Seidman AD, Scher HI, Petrylak D, et al. Estramustine and vinblastine: use of prostate specific antigen as a clinical trial end point for hormone refractory prostatic cancer. J Urol 1992; 147(3 Pt 2): 931-4.
- Atiq O, Lewis B. Treatment of hormone-refractory prostate adenocarcinoma (HRPA) with estramustine and vinblastine (EV) chemotherapy [abstract 744]. Proc Annu Meet Am Soc Clin Oncol 1994; 13: 240.
- Khil MS, Kim JH, Bricker L, et al. Estramustine plus vinblastine as new radiation enhancers in the treatment of locally advanced prostate cancer [abstract 726]. Proc Annu Meet Am Soc Clin Oncol 1993; 13: 235.
- Reese D, Burris H, Belledgrun A, et al. A phase I/II study of Navelbine (vinorelbine) and estramustine in the treatment of hormone refractory prostate cancer (HRPC) [abstract 673]. Proc Annu Meet Am Soc Clin Oncol 1996; 15: 259.
- Colleoni M, Graiff C, Vicario G, et al. Phase II study of estramustine, oral etoposide, and vinorelbine in hormone-refractory prostate cancer. Am J Clin Oncol 1997; 20(4): 383-6.
- Hernes EH, Rossa SD, Vaage S, et al. Epirubicin combined with estramustine phosphate in hormone-resistant prostate cancer: a phase II study. Br J Cancer 1997; 76(1): 93-9.
- Droz JP, Culine S. Evaluation of the activity of a combination of doxorubicin and estramustine phosphate in hormone-refractory prostate [abstract 700]. Proc Annu Meet Am Soc Clin Oncol 1996; 15: 266.
- Hedlund PO, Jacobsson H, Vaage S, et al. Treatment of high-grade, high-stage prostate cancer with estramustine phosphate or diethylstilbestrol. A double-blind study. The SPCG-I study group. Scandinavian Prostate Cancer Group. Scan J Urol Nephrol 1997; 31(2): 167-72.
- Janknegt RA, Boon TA, van de Beck C, et al. Combined hormono/chemotherapy as primary treatment for metastatic prostate cancer: a randomized, multicenter study orchiectomy alone versus orchiectomy plus estramustine phosphate. The Dutch Estracyt Study Group. Urol 1997; 49(3): 411-20.
- Schmidt J, Gibbons R, Murphy C, et al. Adjuvant treatment for localized prostate cancer following radical prostatectomy or definitive irradiation [abstract 706]. Proc Annu Meet Am Soc Clin Oncol 1993; 12: 230.
- Iverson P, Rasmussen F, Asmussen C, et al. Estramustine phosphate versus placebo as second line treatment after orchiectomy in patients with metastatic prostate cancer: DAPROCA study 9002. Danish Prostatic Cancer Group. J Urol 1997; 157(3): 929-34.
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