1. NAME OF THE MEDICINAL PRODUCT

Duphaston®and Duphaston®-HRT


2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg dydrogesterone B.P.


3. PHARMACEUTICAL FORM

Round, white tablet, scored on one side with the imprint '155' on each half of the tablet and imprinted '' on the reverse.


4. CLINICAL PARTICULARS


4.1 Therapeutic indications

To counteract the effects of unopposed oestrogen in hormone replacement therapy, pre-menstrual syndrome, endometriosis, dysmenorrhoea, infertility, irregular cycles, dysfunctional bleeding (with added oestrogen), secondary amenorrhoea (with added oestrogen), threatened and habitual abortion (associated with proven progesterone deficiency).


4.2 Posology and method of administration Adults

Hormone replacement therapy


The standard dose is 10 mg Duphaston daily for the last 14 days of each 28-day oestrogen treatment cycle. The dose may be increased to 10 mg twice daily if either early withdrawal bleeding occurs or if endometrial biopsy reveals inadequate progestational response.

Pre-menstrual syndrome


10 mg twice daily from day 12 to 26 of the cycle. The dosage may be increased if necessary.

Endometriosis


10 mg two to three times daily from day 5 to 25 of the cycle, or continuously.

Dysmenorrhoea


10 mg twice daily from day 5 to 25 of the cycle.

Infertility or Irregular cycles


10 mg twice daily from day 11 to 25 of the cycle. Treatment should be maintained for at least six consecutive cycles. If the patient conceives, it is advisable to continue treatment for the first few months of pregnancy as described under 'habitual abortion'.

Dysfunctional bleeding - to arrest bleeding


10 mg twice daily together with an oestrogen once daily for five to seven days.

Dysfunctional bleeding - to prevent bleeding


10 mg twice daily together with an oestrogen once daily from day 11 to day 25 of the cycle.

Amenorrhoea


An oestrogen once daily from day 1 to 25 of the cycle, and Duphaston 10 mg twice daily from day 11 to 25 of the cycle.

Threatened abortion


40 mg at once then 10 mg every eight hours until symptoms remit. If symptoms persist or return during treatment the dose can be increased by one tablet every eight hours. The effective dose must be maintained for a week after symptoms have ceased and can then be gradually decreased unless symptoms return.

Habitual abortion


Treatment should be started as early as possible, preferably before conception: 10 mg should be given twice daily from day 11 to 25 of the cycle until conception and then continuously (10 mg twice daily) until the twentieth week of pregnancy, then dosage may be gradually reduced.

Elderly


Hormone replacement therapy: Standard adult dosage is recommended.

Children


Primary dysmenorrhoea: 10 mg twice daily at the discretion of the physician.


4.3 Contraindications

Duphaston: None known.

Duphaston-HRT: Known or suspected carcinoma of the breast.


4.4 Special warnings and precautions for use

Duphaston: None known.

Duphaston-HRT: Assessment of each woman prior to taking hormone replacement therapy (and at regular intervals thereafter) should include a personal and family medical history. Physical examination should be guided by this and by the contraindications (section 4.3) and warnings (section 4.4) for this product. During assessment of each individual woman clinical examination of the breasts and pelvic examination should be performed where clinically indicated rather than as a routine procedure. Women should be encouraged to participate in the national breast cancer screening programme (mammography) and the national cervical cancer screening programme (cervical cytology) as appropriate for their age). Breast awareness should also be encouraged and women advised to report any changes in their breasts to their doctor or nurse.

A reanalysis of original data from 51 epidemiological studies reported a small or moderate increase in the probability of having breast cancer diagnosed in women currently or recently using HRT. The findings may be due to biological effects of HRT, earlier diagnosis, or a combination of both. The relative risk increased with duration of treatment (by 2.3% per year of use) and returned to normal in the course of five years after cessation of HRT use. This is comparable to the increase in relative risk when natural menopause is delayed in the absence of HRT. Breast cancers diagnosed in current or recent users of HRT are more likely to be localised to the breast than those found in non-users. HRT use may not be associated with increased mortality from breast cancer.

Between the ages of 50 and 70, about 45 women in every 1000 not using HRT will have breast cancer diagnosed. It is estimated that among those who use HRT for 5 years starting at age 50, 2 extra cases of breast cancer will be detected by age 70 in every 1000 women. For those who use HRT for 10 years there will be 6 extra cases of breast cancer, and for 15 years use, 12 extra cases of breast cancer in every 1000 women during the 20 year period until age 70.

It is important that the increased risk of being diagnosed with breast cancer is discussed with the patient and weighed against the known benefits of HRT.


4.5 Interaction with other medicinal products and other forms of Interaction

None known.


4.6 Pregnancy and lactation

Pregnancy: There is no known risk in pregnancy. Duphaston is indicated for threatened or habitual abortion, until the twentieth week of pregnancy.

Lactation: Small amounts are expected to be excreted, but exact amounts are unknown. There have been no reports of adverse experiences.

4.7 Effects on ability to drive and use machines

None known.


4.8 Undesirable effects

Serious side effects are not expected. Breakthrough bleeding may occur in a few patients. It can, however, be prevented by increasing the dosage. Nausea, breast tenderness, headache, bloated feeling, transient dizziness and skin reactions have occasionally been reported.


4.9 Overdose
Symptoms


No reports of ill-effects from overdosage have been reported and remedial action is generally unnecessary.

Treatment


If a large overdosage is discovered within 2-3 hours and treatment seems desirable, gastric lavage is recommended. There are no special antidotes and treatment should be symptomatic.


5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Dydrogesterone is an orally-active progestogen, which produces a complete secretory endometrium in an oestrogen-primed uterus, thereby providing protection for oestrogen-induced increased risk of endometrial hyperplasia and/or carcinogenesis. It is indicated in all cases of endogenous progesterone deficiency. Duphaston is non-androgenic, non-oestrogenic, non-thermogenic, non-corticoid and non-anabolic.


5.2 Pharmacokinetic properties

After oral administration of labelled dydrogesterone, on average 63% of the dose is excreted into the urine. Within 72 hours, excretion is complete. Dydrogesterone is completely metabolised.

The main metabolite of dydrogesterone is 20α-dihydrodydrogesterone (DHD) and is present in the urine predominantly as the glucuronic acid conjugate. A common feature of all metabolites characterised is the retention of the 4,6 diene-3-one configuration of the parent compound and the absence of 17α-hydroxylation. This explains the lack of oestrogenic and androgenic effects of dydrogesterone.

After oral administration of dydrogesterone, plasma concentrations of DHD are substantially higher as compared to the parent drug. The AUC and Cmax ratios of DHD to dydrogesterone are in the order of 40 and 25, respectively.

Dydrogesterone is rapidly absorbed. The Tmax values of dydrogesterone and DHD vary between 0.5 and 2.5 hours.

Mean terminal half lives of dydrogesterone and DHD vary between 5 to 7 and 14 to 17 hours, respectively.

Unlike progesterone, dydrogesterone is not excreted in the urine as pregnanediol. It is therefore possible to analyse production of endogenous progesterone even in the presence of dydrogesterone.

5.3 Preclinical safety data

Dydrogesterone has been used in several animal models and has been proven to be an entity with low toxicity, not having mutagenic or carcinogenic properties.

No effects were seen in reproduction experiments.




6. PHARMACEUTICAL PARTICULARS

6.1 List of excipient(s)

Lactose, maize starch, methylhydroxypropylcellulose, polyethylene glycol 400, silica, magnesium stearate, titanium dioxide (E171).



6.2 Incompatibilities

Not applicable.


6.3 Shelf-life

Five years.


6.4 Special precautions for storage

Do not store above 30°C. Store in the original package.


6.5 Nature and contents of container

Cartons containing 42 (Duphaston-HRT) or 60 (Duphaston) tablets in blister strips.

6.6 Instructions for use and handling

None.

7. MARKETING AUTHORISATION HOLDER

Solvay Healthcare Limited

Mansbridge Road

West End

Southampton

SO18 3JD

8. MARKETING AUTHORISATION NUMBER(S)

PL 00512/5004R

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17 October 1995

10. DATE OF REVISION OF THE TEXT

May 2001

Legal category

POM