Estramustine
140mg Capsules

What Estramustine is and what it is used for

Estramustine is one of a group of medicines called cytotoxics; these medicines are used in the treatment of cancer.

Estramustine is used to treat cancer of the prostate gland.
You should consult your doctor if you are unsure why you have been given Estramustine.

What you need to know before you take Estramustine

Do not take Estramustine if you:

• are allergic (hypersensitive) to any of the ingredients of Estramustine, (listed in section 6), or oestradiol or nitrogen mustard
• have an ulcer in the stomach or intestines · have a serious heart disease
• have a serious liver disease
• are having problems related to blood clots
• are suffering from problems caused by fluid retention.

Estramustine is not suitable for use in children.
Since Estramustine is used to treat prostate cancer in males, Estramustine is not indicated for women.

If you are unsure what this means, speak to your doctor or pharmacist.

Warnings and Precautions
Talk to your doctor or pharmacist before you start taking Estramustine if you suffer from or have suffered in the past from any of the following conditions:

• your bone marrow is not working well, or you have been told that you have low blood cell counts
• you have had problems with blood clots or sore veins
• you have been diagnosed with cerebral vascular disease (a condition which can sometimes lead to a ‘stroke’)
• you have diabetes
• you have or have had high blood pressure · you are an epileptic
• you have or have had a high level of calcium in your blood · you have or have had kidney disease
• you have fluid retention
• you have heart problems which can cause shortness of breath or ankle swelling · you suffer from migraines
• you have had or you are due to have any vaccination including a live or live-attenuated vaccination.

Regular Check-ups
Your doctor may need to test your blood, liver function and the level of calcium in your blood. He/she will tell you how often this should be done.

Other medicines and Estramustine
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription

Some medicines can affect the way Estramustine works, or Estramustine itself can reduce the effectiveness of other medicines if taken at the same time. You should tell your doctor if you are taking any of the following medicines:

• Certain medicines used for the treatment of depression (tricyclic anti-depressants).
• Medicines containing calcium, magnesium or aluminium such as some indigestion remedies.
• Medicines known as ACE Inhibitors used to treat high blood pressure or heart disease.

Taking Estramustine with food and drink
Your capsules will work less well if you have calcium in your stomach. Calcium is found in milk, dairy products such as cheese and some indigestion remedies, make sure that you check the ingredients listed on the label. (see further information in section 3. How to take Estramustine).

Pregnancy and breast-feeding
Since Estramustine is used to treat prostate cancer in males, it is not intended for use in women.

Pregnancy should be avoided while you are being treated with Estramustine. If, during treatment, you are sexually active, both you and your partner are advised to use effective birth control to prevent pregnancy. Estramustine may cause birth defects, so it is important to tell your doctor if you think your partner is pregnant.

If your partner is breast-feeding during your treatment use a reliable form of barrier contraception while on this medication. Consult your doctor if you have any questions about this medication.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

There is currently no evidence which suggests that Estramustine is likely to affect your ability to drive or use machines.

Ask your doctor or pharmacist for advice before taking any medicine.

How to take Estramustine

Always take Estramustine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are still not sure. It is best to take Estramustine at the same time each day.

Adults and the Elderly
Usually four to six capsules a day, taken at separate times, are used to start treatment. Depending on how your illness responds and how well you tolerate the medicine, your doctor may change the dose to anywhere between one and ten capsules a day. You may also find this information on the label.

The capsules should be taken on an empty stomach. The capsules should be taken at least one hour before a meal, or more than two hours after a meal. The capsules should be swallowed whole with a glass of water. Do not attempt to split open the capsules.

Do not take your medicine with milk or other drinks containing milk such as tea or coffee (see ‘Taking Estramustine with food and drink’ above). Furthermore, do not take Estramustine at the same time as other medicines which contain calcium, magnesium or aluminium e.g. antacids (see ‘Taking other medicines’ above.)

Use in Children
Estramustine is not suitable for use in children.

If you take more Estramustine than you should
If you accidentally take too much Estramustine contact your doctor at once or go to the nearest hospital casualty department (since the stomach may need to be emptied and any symptoms of the overdose treated). Always take the labelled medicine package with you, whether there is any Estramustine left or not.

If you forget to take Estramustine
If you forget to take a dose, take it as soon as you remember unless it is time for your next dose. Do not take a double dose to make up for a missed dose.

If you stop taking Estramustine
Do not stop taking Estramustine unless your doctor tells you to. Your doctor will tell you how long you should take Estramustine for. Should you need to stop taking Estramustine, your doctor will decide which is the best method for you.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Reasons for contacting your doctor immediately
Some side effects occur rarely but can potentially be very serious. Tell your doctor immediately if you experience:

• an allergic reaction such as sudden wheeziness, difficulty in breathing, swelling of eyelids, face or lips, rash or itching (especially affecting the whole body)
• increasing swelling, discomfort or discolouration of one or both legs · chest pain or breathlessness.

The most common side effects are:

• discomfort and/or some swelling of the breasts
• decrease in sexual function
• nausea (feeling sick) and vomiting (being sick), mostly in the first 2 weeks of treatment
• fluid build-up in the body, causing swollen ankles and legs.

Other side-effects that may occur are:

• heart failure, heart attack, blood clots in your blood vessels and increased blood pressure
• diarrhoea.
• reduced liver function
• reduction in red blood cells (anaemia) and certain white blood cells rarely occur
• reduction in number of platelets that help your blood to clot
• muscular weakness, depression, headache, confusion and tiredness rarely occur.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

How to store Estramustine

Keep out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

Contents of the pack and other information

What Estramustine contains
The active substance is estramustine phosphate. Each capsule contains 140mg of estramustine phosphate (as estramustine sodium phosphate).

The other ingredients are: talc, sodium lauryl sulphate, colloidal silicon dioxide, magnesium stearate, gelatin, titanium dioxide (E171), black ink (containing shellac, black iron oxide (E172), ammonium hydroxide (E527) and propylene glycol (E1520)).

What Estramustine looks like and contents of the pack
Estramustine are white, hard gelatin capsules with “TAJ” written in black ink and are available in bottles containing 100 capsules.

Estramustine
140mg Capsules

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(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:

CLINICAL PHARMACOLOGY

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.

INDICATIONS AND USAGE

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

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.

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 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.

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.

ADVERSE REACTIONS

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:

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 6 weeks after overdosage of EMCYT Capsules.

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 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.

HOW SUPPLIED

White opaque capsules, each containing estramustine phosphate sodium as the disodium salt monohydrate equivalent to 140 mg estramustine phosphate—bottle of 100.

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.