SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Estracyt Capsules.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Estramustine phosphate 140 mg as estramustine sodium phosphate.

3 PHARMACEUTICAL FORM

White, hard, gelatin capsules.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Carcinoma of the prostate, especially in cases unresponsive to, or relapsing after, treatment by conventional oestrogens (stilboestrol, polyestradiol phosphate etc.) or by orchidectomy

4.2 Posology and method of administration

Adult and the elderly

Dosage range may be from 1 to 10 capsules a day by mouth. The capsules should be taken not less than 1 hour before or 2 hours after meals. Milk, milk products or drugs containing calcium, magnesium or aluminium (e.g. antacids) must not be taken simultaneously with Estracyt® capsules (see section 4.5). Standard starting dosage is 4-6 capsules a day in divided doses with later adjustment according to response and gastrointestinal tolerance.

Children

Estracyt should not be administered to children.

4.3 Contraindications

Use in patients with peptic ulceration, or those with severe liver dysfunction or myocardial insufficiency.

Use in patients with active thrombosis or thromboembolic disorders or complications related to fluid retention.

Use in children.

Use in patients hypersensitive to oestradiol or nitrogen mustard.

4.4 Special warnings and precautions for use

Estramustine should be used with caution in patients with a history of thrombophelebitis, thrombosis or thromboembolic disorders, especially if associated with estrogen therapy. Caution should also be used in patients with cardiovascular disease, cerebral vascular disease and coronary artery disease.

Glucose Tolerance - Because glucose tolerance may be decreased, diabetic patients should be carefully followed while receiving estramustine.

Elevated blood pressure - Because hypertension may occur, blood pressure should be monitored periodically.

Fluid retention - Exacerbation of pre-existing or incipient peripheral oedema or congestive heart disease has been seen in some patients receiving estramustine therapy. Other conditions which might be influenced by fluid retention, such as epilepsy, migraine, or renal dysfunction, require careful observation.

Calcium/phosphorous metabolism - Estramustine may influence the metabolism of calcium and phosphorous and should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia or in patients with renal insufficiency. Serum calcium should be performed at regular intervals. Patients with prostate cancer and osteoblastic metastases are at risk for hypocalcemia and should have calcium levels closely monitored.

Estramustine may be poorly metabolized in patients with impaired liver function and should be administered with caution in such patients. Liver function tests should be performed at regular intervals.

Note: since certain endocrine and hepatic functions are influenced by estrogen-containing drugs the corresponding laboratory test values will be affected.

Use with caution in patients with moderate to severe bone marrow depression. Blood count should be performed at regular intervals.

Immunosuppressant Effects/Increased Susceptibility to Infections - Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including estramustine, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving estramustine. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

4.5 Interaction with other medicinal products and other forms of interaction

Oestrogens have been reported to increase both therapeutic activity and toxicity of tricyclic antidepressants, probably via inhibition of their metabolism.

Milk, milk products or drugs containing calcium, magnesium or aluminium may impair the absorption of Estracyt^® and simultaneous intake must therefore be avoided. The mechanism behind this interaction is that estramustine forms insoluble salts with polyvalent metal ions.

An interaction between Estracyt and ACE-inhibitors, possibly leading to an increased risk of angioneurotic oedema cannot be excluded.

4.6 Pregnancy and lactation

Estradiol and nitrogen mustard are potentially mutagenic, and therefore males undergoing treatment with estramustine should employ contraceptive measures (See section 5.3).

Since Estracyt is indicated for carcinoma of the prostate in males, it is not indicated for women

4.7 Effects on ability to drive and use machines

The effect of estramustine on the ability to drive or use machinery has not been systematically evaluated.

4.8 Undesirable effects

The most common adverse reactions include gynaecomastia and impotence, nausea/vomiting and fluid retention/oedema.

The most serious reactions are thromboembolism, ischaemic heart disease, congestive heart failure and, rarely and angioneurotic oedema.

Reported reactions arranged according to MedDRA System Organ Class are the following:

Blood and lymphatic system disorders: Anemia, leukopenia, thrombocytopenia rarely occur.

Immune system disorders: Hypersensitivity reaction

Metabolism and nutrition disorders: Fluid retention

Psychiatric disorders: Confusion and depression rarely occur.

Nervous system disorders: Headache and lethargy rarely occur

Cardiac disorders: Congestive heart failure, ischemic heart disease, myocardial infarction

Vascular disorders: Hypertension, thromboembolism

Gastrointestinal disorders: Nausea and vomiting, diarrhea (particularly during the first two weeks of treatment)

Hepato-biliary disorders: Impairment of liver function

Skin and subcutaneous tissue disorders: Allergic skin rash.

Angioneurotic edema (Quincke edema, larynx edema) can rarely occur. In many reported cases, including a fatal one, patients were concomitantly receiving ACE-inhibitors. Therapy with Estracyt is to be immediately discontinued should angioneurotic edema occur.

Musculoskeletal and connective tissue disorders: Muscular weakness rarely occurs.

Reproductive system and breast disorders: Gynecomastia, impotence

4.9 Overdose

There is no specific antidote. Treatment is symptomatic and supportive (as necessary the gastric contents should be evacuated by gastric lavage) and in the event of dangerously low red cell, white cell or platelet count, whole blood should be given as necessary. Liver function should be monitored.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: L01XX11

Estracyt is a chemical compound of oestradiol and nitrogen mustard. It is effective in the treatment of advanced prostatic carcinoma.

Estracyt has a dual mode of action. The intact molecule acts as an anti-miotic agent; after hydrolysis of the carbamate ester, the metabolites act to bridge the released oestrogens and exert an anti-gonadotrophic effect. The low level of clinical side effects may be due to the fact that estramustine binds to a protein present in the tumour tissue, so resulting in accumulation of the drug at the target site. Estracyt also has weak oestrogenic and anti-gonadotrophic properties.

Estracyt causes little or no bone marrow depression at usual therapeutic dosage. Estracyt is effective in patients who have not previously received drug therapy, as well as in those who have shown no response to conventional hormone treatment.

5.2 Pharmacokinetic properties

Estramustine phosphate sodium is rapidly dephosphorylated in the intestine and prostate to estramustine and estromustine, which accumulate in the prostatic tissue. The plasma half-lives of these metabolites are 10 - 20 hours. Estramustine and estromustine are further metabolised before excretion.

5.3 Preclinical safety data

In repeat dose toxicity studies in rats, dogs and monkeys the main target organs are the hemolymphopoietic and endocrine systems and male and female reproductive organs, with changes related to both oestrogenic and cytotoxic effects of estramustine phosphate.

No reproduction or oncogenicity studies have been undertaken and the mutagenicity of the compound has not fully been investigated. Nevertheless estramustine phosphate, like other oestrogenic and antimitotic agents, must be considered toxic to the reproductive organs and potentially mutagenic and carcinogenic.

6.1 List of excipient(s)

Talcum, sodium lauryl sulphate, colloidal silicon dioxide, magnesium stearate, titanium dioxide (E171), hard gelatin capsule, black ink (containing black iron

oxide (E172), ammonium hydroxide (E527), propylene glycol (E1520) and shellac).

6.2 Incompatibilities

None that are relevant.

6.3 Shelf life

60 months in brown glass bottles.

6.4 Special precautions for storage

Store out of the sight and reach of children.

The product is stable at storage conditions of 25^oC + 2^oC/60%RH (long term) and 40^oC + 2^oC/75%RH (short term). Therefore the product does not require any special storage precautions within EU countries (Climactic zone 2).

6.5 Nature and contents of container

Brown glass bottle containing 100 capsules.

6.6 Special precautions for disposal

No special instructions.

7    MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road Sandwich Kent CT13 9NJ United Kingdom

MARKETING AUTHORISATION NUMBER(S)

PL 00057/0973

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/11/2008

DATE OF REVISION OF THE TEXT

05/09/2013