DRUG INTERACTIONS SECTION.

Food/Drug Interaction. Milk, milk products, and calcium-rich foods or drugs may impair the absorption of EMCYT.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. In randomized, double-blind trial comparing therapy with EMCYT Capsules in 93 patients (11.5 to 15.9 mg/kg/day) or diethylstilbestrol (DES) in 93 patients (3.0 mg/day), the following adverse effects were reported:EMCYTn=93DESn=93CARDIOVASCULAR-RESPIRATORY Cardiac Arrest02 Cerebrovascular Accident20 Myocardial Infarction31 Thrombophlebitis37 Pulmonary Emboli25 Congestive Heart Failure32 Edema1917 Dyspnea113 Leg Cramps811 Upper Respiratory Discharge11 Hoarseness10GASTROINTESTINAL Nausea158 Diarrhea1211 Minor Gastrointestinal Upset116 Anorexia43 Flatulence20 Vomiting11 Gastrointestinal Bleeding10 Burning Throat10 Thirst10INTEGUMENTARY Rash14 Pruritus22 Dry Skin20 Pigment Changes03 Easy Bruising30 Flushing10 Night Sweats01 Fingertip--Peeling Skin10 Thinning Hair11BREAST CHANGES Tenderness6664 Enlargement Mild6054 Moderate1016 Marked05MISCELLANEOUS Lethargy Alone43 Depression02 Emotional Lability20 Insomnia30 Headache11 Anxiety10 Chest Pain11 Hot Flashes01 Pain in Eyes01 Tearing of Eyes11 Tinnitus01LABORATORY ABNORMALITIES Hematologic Leukopenia42 Thrombopenia12 Hepatic Bilirubin Alone15 Bilirubin and LDH01 Bilirubin and SGOT21 Bilirubin, LDH and SGOT20 LDH and/or SGOT3128 Miscellaneous Hypercalcemia--Transient01.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term continuous administration of estrogens in certain animal species increases the frequency of carcinomas of the breast and liver. Compounds structurally similar to EMCYT are carcinogenic in mice. Carcinogenic studies of EMCYT have not been conducted in man. Although testing by the Ames method failed to demonstrate mutagenicity for estramustine phosphate sodium, it is known that both estradiol and nitrogen mustard are mutagenic. For this reason and because some patients who had been impotent while on estrogen therapy have regained potency while taking EMCYT, the patient should be advised to use contraceptive measures.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Estramustine phosphate (Figure 1) is molecule combining estradiol and nornitrogen mustard by carbamate link. The molecule is phosphorylated to make it water soluble.Estramustine phosphate taken orally is readily dephosphorylated during absorption, and the major metabolites in plasma are estramustine (Figure 2), the estrone analog (Figure 3), estradiol, and estrone.Prolonged treatment with estramustine phosphate produces elevated total plasma concentrations of estradiol that fall within ranges similar to the elevated estradiol levels found in prostatic cancer patients given conventional estradiol therapy. Estrogenic effects, as demonstrated by changes in circulating levels of steroids and pituitary hormones, are similar in patients treated with either estramustine phosphate or conventional estradiol.The metabolic urinary patterns of the estradiol moiety of estramustine phosphate and estradiol itself are very similar, although the metabolites derived from estramustine phosphate are excreted at slower rate.. Chemical Structure. Chemical Structure. Chemical Structure.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. EMCYT Capsules should not be used in patients with any of the following conditions:1)Known hypersensitivity to either estradiol or to nitrogen mustard.2)Active thrombophlebitis or thromboembolic disorders, except in those cases where the actual tumor mass is the cause of the thromboembolic phenomenon and the physician feels the benefits of therapy may outweigh the risks.. 1)Known hypersensitivity to either estradiol or to nitrogen mustard.. 2)Active thrombophlebitis or thromboembolic disorders, except in those cases where the actual tumor mass is the cause of the thromboembolic phenomenon and the physician feels the benefits of therapy may outweigh the risks.

DESCRIPTION SECTION.

DESCRIPTION. Estramustine phosphate sodium, an antineoplastic agent, is an off-white powder readily soluble in water. EMCYT Capsules are white and opaque, each containing estramustine phosphate sodium as the disodium salt monohydrate equivalent to 140 mg estramustine phosphate, for oral administration. Each capsule also contains magnesium stearate, silicon dioxide, sodium lauryl sulfate, and talc. Gelatin capsule shells contain the following pigment: titanium dioxide.Chemically, estramustine phosphate sodium is estra-1,3,5(10)-triene-3,17-diol(17)-,3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate. It is also referred to as estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate. Estramustine phosphate sodium has an empiric formula of C23H30Cl2NNa2O6PoH2O, calculated molecular weight of 582.4, and the following structural formula:. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. The recommended daily dose is 14 mg per kg of body weight (ie, one 140 mg capsule for each 10 kg or 22 lb of body weight), given in or divided doses. Most patients in studies in the United States have been treated at dosage range of 10 to 16 mg per kg per day.Patients should be instructed to take EMCYT Capsules at least hour before or hours after meals. EMCYT should be swallowed with water. Milk, milk products, and calcium-rich foods or drugs (such as calcium-containing antacids) must not be taken simultaneously with EMCYT.Patients should be treated for 30 to 90 days before the physician determines the possible benefits of continued therapy. Therapy should be continued as long as the favorable response lasts. Some patients have been maintained on therapy for more than years at doses ranging from 10 to 16 mg per kg of body weight per day.Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

GENERAL PRECAUTIONS SECTION.

General. Fluid Retention. Exacerbation of preexisting or incipient peripheral edema or congestive heart disease has been seen in some patients receiving therapy with EMCYT Capsules. Other conditions which might be influenced by fluid retention, such as epilepsy, migraine, or renal dysfunction, require careful observation.EMCYT may be poorly metabolized in patients with impaired liver function and should be administered with caution in such patients.Because EMCYT may influence the metabolism of calcium and phosphorus, it should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia or in patients with renal insufficiency. Patients with prostate cancer and osteoblastic metastases are at risk for hypocalcemia and should have calcium levels closely monitored.Gynecomastia and impotence are known estrogenic effects.Allergic reactions and angioedema at times involving the airway have been reported.

HOW SUPPLIED SECTION.

HOW SUPPLIED. White opaque capsules, each containing estramustine phosphate sodium as the disodium salt monohydrate equivalent to 140 mg estramustine phosphate--bottle of 100 (NDC 0013-0132-02).NOTEEMCYT Capsules should be stored in the refrigerator at 36 to 46F (2 to 8C).

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. EMCYT Capsules are indicated in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate.

INFORMATION FOR PATIENTS SECTION.

Information for the Patient. Because of the possibility of mutagenic effects, patients should be advised to use contraceptive measures.

LABORATORY TESTS SECTION.

Laboratory Tests. Certain endocrine and liver function tests may be affected by estrogen-containing drugs. EMCYT may depress testosterone levels. Abnormalities of hepatic enzymes and of bilirubin have occurred in patients receiving EMCYT. Such tests should be done at appropriate intervals during therapy and repeated after the drug has been withdrawn for two months.

OVERDOSAGE SECTION.

OVERDOSAGE. Although there has been no experience with overdosage to date, it is reasonable to expect that such episodes may produce pronounced manifestations of the known adverse reactions. In the event of overdosage, the gastric contents should be evacuated by gastric lavage and symptomatic therapy should be initiated. Hematologic and hepatic parameters should be monitored for at least weeks after overdosage of EMCYT Capsules.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 140 mg Capsule Bottle Label. PfizerNDC 0013-0132-02Emcyt(R)capsules140 mgestramustine phosphatesodium capsules100 CapsulesRx only. PRINCIPAL DISPLAY PANEL 140 mg Capsule Bottle Label.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Fluid Retention. Exacerbation of preexisting or incipient peripheral edema or congestive heart disease has been seen in some patients receiving therapy with EMCYT Capsules. Other conditions which might be influenced by fluid retention, such as epilepsy, migraine, or renal dysfunction, require careful observation.EMCYT may be poorly metabolized in patients with impaired liver function and should be administered with caution in such patients.Because EMCYT may influence the metabolism of calcium and phosphorus, it should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia or in patients with renal insufficiency. Patients with prostate cancer and osteoblastic metastases are at risk for hypocalcemia and should have calcium levels closely monitored.Gynecomastia and impotence are known estrogenic effects.Allergic reactions and angioedema at times involving the airway have been reported.. Information for the Patient. Because of the possibility of mutagenic effects, patients should be advised to use contraceptive measures.. Laboratory Tests. Certain endocrine and liver function tests may be affected by estrogen-containing drugs. EMCYT may depress testosterone levels. Abnormalities of hepatic enzymes and of bilirubin have occurred in patients receiving EMCYT. Such tests should be done at appropriate intervals during therapy and repeated after the drug has been withdrawn for two months.. Food/Drug Interaction. Milk, milk products, and calcium-rich foods or drugs may impair the absorption of EMCYT.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term continuous administration of estrogens in certain animal species increases the frequency of carcinomas of the breast and liver. Compounds structurally similar to EMCYT are carcinogenic in mice. Carcinogenic studies of EMCYT have not been conducted in man. Although testing by the Ames method failed to demonstrate mutagenicity for estramustine phosphate sodium, it is known that both estradiol and nitrogen mustard are mutagenic. For this reason and because some patients who had been impotent while on estrogen therapy have regained potency while taking EMCYT, the patient should be advised to use contraceptive measures.

REFERENCES SECTION.

REFERENCES. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC, 20402.AMA Council Report, Guidelines for Handling Parenteral Antineoplastics, JAMA. 1985; 253 (11):1590-1592.National Study Commission on Cytotoxic Exposure-Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med Australia. 1983; 1:426-428.Jones RB, et al. Safe Handling of Chemotherapeutic Agents: Report from the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians. 1983; (Sept/Oct) 258-263.American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am Hosp Pharm. 1990; 47:1033-1049.OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. Am Hosp Pharm. 1986; 43:1193-1204.ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC, 20402.. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics, JAMA. 1985; 253 (11):1590-1592.. National Study Commission on Cytotoxic Exposure-Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med Australia. 1983; 1:426-428.. Jones RB, et al. Safe Handling of Chemotherapeutic Agents: Report from the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians. 1983; (Sept/Oct) 258-263.. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am Hosp Pharm. 1990; 47:1033-1049.. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. Am Hosp Pharm. 1986; 43:1193-1204.. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.

SPL UNCLASSIFIED SECTION.

Rx onlyLAB-0088-4.0June 2007. Logo.

WARNINGS SECTION.

WARNINGS. It has been shown that there is an increased risk of thrombosis, including fatal and nonfatal myocardial infarction, in men receiving estrogens for prostatic cancer. EMCYT Capsules should be used with caution in patients with history of thrombophlebitis, thrombosis, or thromboembolic disorders, especially if they were associated with estrogen therapy. Caution should also be used in patients with cerebral vascular or coronary artery disease.Glucose Tolerance--Because glucose tolerance may be decreased, diabetic patients should be carefully observed while receiving EMCYT.Elevated Blood Pressure--Because hypertension may occur, blood pressure should be monitored periodically.