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(17β)-,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 C₂₃H₃₀Cl₂NNa₂O₆P•H₂O, a calculated molecular weight of 582.4, and the following structural formula:

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

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 3 or 4 divided doses. Most patients in studies in the United States have been treated at a dosage range of 10 to 16 mg per kg per day.

Patients should be instructed to take EMCYT Capsules at least 1 hour before or 2 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 3 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.

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).

Note

EMCYT Capsules should be stored in the refrigerator at 36° to 46°F (2° to 8°C).

REFERENCES

1. 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.

2. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics, JAMA. 1985; 253 (11):1590-1592.

3. 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.

4. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia. 1983; 1:426-428.

5. Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians. 1983; (Sept/Oct) 258-263.

6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033- 1049.

7. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. Am J Hosp Pharm. 1986; 43:1193-1204.

8. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.

Pharmacia & Upjohn Company, Division of Pfizer Inc, NY, NY 10017. Revised June 2007. FDA Rev date: 07/09/08.

In a 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:

Food/Drug Interaction

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

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 a 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.

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.

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.

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.

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 6 weeks after overdosage of EMCYT Capsules.

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.

Estramustine phosphate (Figure 1) is a molecule combining estradiol and nornitrogen mustard by a 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 a slower rate.

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

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ESTRAMUSTINE PHOSPHATE - ORAL

(ess-TRAM-you-steen FOSS fate)

COMMON BRAND NAME(S): Emcyt

USES: This medication is used to treat some types of prostate cancer. In the body, estramustine breaks down into estrogens (estrone, estradiol) and a type of cancer drug (estromustine). This medication is thought to work by increasing estrogens, which interfere with prostate cancer, and by slowing/stopping the growth of cancer cells.

HOW TO USE: Take this medication by mouth on an empty stomach, either 1 hour before or 2 hours after a meal, usually 3-4 times a day or as directed by your doctor.

Take this medication with a full glass of water (8 ounces or 240 milliliters) unless your doctor directs you otherwise. Do not lie down for 30 minutes after taking this medication.

Take this medication regularly in order to get the most benefit from it. Remember to take it at the same times each day as directed. The dosage is based on your medical condition, weight, and response to therapy.

Take this medication 3 hours before or after taking any products containing magnesium, aluminum, or calcium. Some examples include quinapril, didanosine, vitamins/minerals, and antacids. Dairy products (e.g., milk, yogurt), calcium-enriched juice, sucralfate, bismuth subsalicylate, iron, and zinc are also included. These products bind with estramustine, preventing its full absorption.

Do not increase your dose or take this medication more often than prescribed. Your condition will not improve any faster, and the risk of serious side effects may be increased.

SIDE EFFECTS: Nausea, vomiting, loss of appetite, flushing, dry skin, headache, leg cramps, decreased sexual interest/ability, and male breast tenderness/enlargement may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes (e.g., depression), swelling of hands/feet, worsening of seizures, signs of worsening diabetes control (e.g., increased thirst and urination).

This medication may infrequently cause serious problems such as heart attacks, stroke, and blood clots. Seek immediate medical attention if you experience any of the following symptoms: chest/jaw/left arm pain, sudden severe headache, weakness on one side of the body, confusion, slurred speech, sudden vision changes (e.g., double vision, loss of vision), pain/redness/swelling of legs, shortness of breath, coughing up blood, sudden dizziness/fainting.

Tell your doctor immediately if any of these rare but very serious side effects occur: easy bruising/bleeding, stomach/abdominal pain, persistent nausea/vomiting, dark urine, yellowing eyes/skin.

This medication can lower the body's ability to fight an infection. Notify your doctor promptly if you develop any signs of an infection such as fever, chills, or persistent sore throat.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking estramustine, tell your doctor or pharmacist if you are allergic to it; or to estradiol or other estrogens; or to nitrogen mustard (e.g., mechlorethamine); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: history of stroke or other blood clots (e.g., in the legs, eyes, lungs), bone disease (e.g., bone metastases, high calcium levels), high cholesterol or triglyceride (blood fat) levels, depression, diabetes, severe headaches (e.g., migraine), heart disease (e.g., angina, heart attack, heart failure), high blood pressure, kidney disease, liver disease, seizure, long periods of sitting or lying down (e.g., immobility such as being bedridden), stroke, thyroid problems.

Do not smoke cigarettes or use tobacco. Estrogens combined with smoking further increase your risk for stroke, blood clots, high blood pressure, and heart attacks.

If you will be having surgery or will be confined to a chair or bed for a long time (e.g., a long plane flight), notify your doctor beforehand. Special precautions may need to be taken in these circumstances while you are taking this drug because of the increased risk for blood clots.

If you have diabetes, estramustine may worsen control of blood glucose levels. Monitor your blood glucose levels regularly and inform your doctor of the results.

If you are nearsighted or wear contact lenses, you may develop vision problems or trouble wearing your contact lenses. Contact your eye doctor if these problems occur.

This drug may cause a patchy darkening of the skin on the face (melasma). Sunlight may worsen this darkening. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

This medication may affect the production of sperm. Use a reliable form of birth control while on this medication. Consult your doctor.

Estramustine is not recommended for use in women and must not be used during pregnancy. Since this drug can be absorbed through the skin and lungs, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the capsules.

Because this drug is not indicated for use in women, it is not known if estramustine passes into breast milk. Consult your doctor before breast-feeding

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: aromatase inhibitors (e.g., anastrazole, exemestane), sodium tetradecyl sulfate, troleandomycin.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting this medication.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: corticosteroids (e.g., prednisolone), raloxifene, tamoxifen, medication for low thyroid (hypothyroidism).

Certain drugs can affect the estrogen levels in your system. Drugs that may cause this effect include: azole antifungals (e.g., itraconazole, ketoconazole), many antibiotics (e.g., cephalosporins, chloramphenicol, macrolides, penicillins, tetracyclines, sulfas), aprepitant, bexarotene, bosentan, dapsone, griseofulvin, certain HIV protease inhibitors (e.g., amprenavir, nelfinavir, ritonavir), modafinil, nevirapine, rifamycins (e.g., rifampin), many seizure medications (e.g., barbiturates, carbamazepine, phenytoin, primidone, topiramate), St John's wort.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory tests (e.g., blood pressure, liver function tests, calcium levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store the U.S. product in the refrigerator between 36-46 degrees F (2-8 degrees C) away from light and moisture. Do not store in the bathroom.

Store the Canadian product between degrees 36-77 degrees F (2-25 degrees C) away from light and moisture. Do not store in the bathroom.

Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.