This information is intended for use by health professionals

1. Name of the medicinal product

Estracyt Capsules.

2. Qualitative and quantitative composition

Estramustine phosphate 140 mg as estramustine sodium phosphate.

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Capsule

White, hard, gelatin capsules with “ESTRACYT” and “K Ph 750” printed in black ink.

4. Clinical particulars
4.1 Therapeutic indications

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

4.2 Posology and method of administration

Posology

Adults 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.

Paediatric population

Estracyt should not be administered to children.

4.3 Contraindications

Hypersensitivity to estramustine sodium phosphate, oestradiol or nitrogen mustard or to any of the excipients listed in section 6.1.

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.

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 hypocalcaemia 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 estramustine and ACE-inhibitors, possibly leading to an increased risk of angioedema (see section 4.8) cannot be excluded.

4.6 Fertility, 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, nausea/vomiting and fluid retention/oedema.

The most serious reactions are embolism, myocardial ischaemia, cardiac failure congestive and angioedema.

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

System Organ Class

Very Common

≥ 1/10

Common

≥ 1/100 to < 1/10

Frequency not known (cannot be estimated from available data)

Blood and lymphatic system disorders

Anaemia, Leukopenia

Thrombocytopenia

Immune system disorders

Hypersensitivity

Metabolism and nutrition disorders

Fluid retention

Psychiatric disorders

Confusional state, Depression

Nervous system disorders

Lethargy, Headache

Cardiac disorders

Cardiac failure congestive

Myocardial infarction

Myocardial ischaemia

Vascular disorders

Embolism

Hypertension

Gastrointestinal disorders

Nausea and Vomiting*, Diarrhoea*

Hepatobiliary disorders

Hepatic function abnormal

Skin and subcutaneous tissue disorders

Angioedema**, Dermatitis allergic

Musculoskeletal and connective tissue disorders

Muscular weakness

Reproductive system and breast disorders

Gynaecomastia

Erectile dysfunction

General disorders and administration site conditions

Injection site thrombosis (IV solution)

*Particularly during the first two weeks of treatment.

**Angioedema (Quincke oedema, larynx oedema) can occur. In many reported cases, including a fatal one, patients were concomitantly receiving ACE-inhibitors. Therapy with estramustine is to be immediately discontinued should angioedema occur.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

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

Pharmacotherapeutic group: 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. Pharmaceutical particulars
6.1 List of excipients

Talcum

Sodium lauryl sulfate

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

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Brown glass bottle containing 100 capsules.

6.6 Special precautions for disposal and other handling

No special requirements.

Any unused medicinal product or waste product should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Pfizer Limited

Ramsgate Road, Sandwich, Kent

CT13 9NJ

UK

8. Marketing authorisation number(s)

PL 00057/0973

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 25 May 2002

Date of latest renewal: 13 Nov 2008

10. Date of revision of the text

01/2016

Legal category

POM

Ref ES 8_2 UK