Abbott Healthcare Products Limited

Duphaston 10 mg Film-Coated Tablets

Each tablet contains 10 mg Dydrogesterone.

Excipients: each tablet contains 111.1mg lactose monohydrate. For a full list of excipients, see section 6.1

Film-coated tablet.

A round, biconvex, scored, white film-coated tablet, one side with inscription “155” on either side of the score.

The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

In the management of conditions associated with progesterone insufficiency: dysmenorrhoea, endometriosis, infertility, irregular menstrual cycles.

The drug may be used with an estrogen in the management of dysfunctional bleeding or secondary amenorrhoea, or in association with estrogen in hormone replacement therapy.

Hormone replacement therapy:

The standard dose is 10 mg Duphaston daily for the last 14 days of each 28-day estrogen 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.

In women who are not taking hormone replacement therapy, have established amenorrhoea or women who switch from a continuous combined hormone replacement therapy, treatment may be started on any convenient day. In women transferring from a cyclic or continuous sequential HRT regimen, treatment should begin the day following completion of the prior regimen. If the patient is menstruating, treatment is started within five days of the start of bleeding.

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used.

Dysfunctional bleeding:

To arrest bleeding - 10 mg b.d.(twice a day) together with an estrogen once daily for five to seven days.

To prevent bleeding - 10 mg b.d. together with an estrogen once daily from day 11 to day 25 of the cycle.

Dysmenorrhoea:

10 mg b.d. from day 5 to 25 of the cycle.

Amenorrhoea:

An estrogen once daily from day 1 to 25 of the cycle, and Duphaston 10 mg b.d. from day 11 to 25.

Endometriosis:

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

Infertility or irregular cycles:

10 mg b.d. from day 11 to 25 of the cycle. Treatment should be maintained for at least six consecutive cycles. After conception, it is advisable to continue treatment, 10 mg b.d. until week 20 of pregnancy, then the dosage may be gradually reduced.

Pre-menstrual syndrome:

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

Forgotten dose:

If a dose has been forgotten, it should be taken as soon as possible. When more than 12 hours have elapsed, it is recommended to continue with the next dose without taking the forgotten tablet. The likelihood of breakthrough bleeding or spotting may be increased.

Duphaston is not recommended for use in children below age 18 due to insufficient data on safety and efficacy.

• Known hypersensitivity to the active substances or to any of the excipients.

• Known or suspected progestogen dependant neoplasms.

• Use in patients with active deep vein thrombosis, thromboembolic disorders, breast or genital cancer (known or suspected to be hormone-dependent), or a past history of these conditions.

• Use in patients with undiagnosed irregular vaginal bleeding.

When used in conjunction with an oestrogen, the contraindications relating to the particular oestrogen used should also be considered, for example:

• Known, past or suspected breast cancer;

• Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer);

• Undiagnosed genital bleeding;

• Untreated endometrial hyperplasia;

• Previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary embolism);

• Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction);

• Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal;

• Porphyria.

Treatment with dydrogesterone has in frequently been associated with alterations in liver function, sometimes accompanied by clinical symptoms. Thus, dydrogesterone should be used with caution in patients with acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal. In cases of severe hepatic impairment treatment should be discontinued.

Breakthrough bleeding may occur in a few patients. This can, however, be prevented by increasing the dosage.

A decreased glucose tolerance may occur in diabetic patients on this treatment and their control must be carefully supervised.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

When used in conjunction with an estrogen, the special warnings and precautions for use relating to the particular estrogen used should also be considered, for example:

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

Medical examination/follow up:

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'breast cancer' below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision:

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Duphaston, in particular:

- Leiomyoma (uterine fibroids) or endometriosis.

- A history of, or risk factors for, thromboembolic disorders (see below).

- Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer.

- Hypertension.

- Liver disorders (e.g. liver adenoma).

- Diabetes mellitus with or without vascular involvement.

- Cholelithiasis.

- Migraine or (severe) headache.

- Systemic lupus erythematosus.

- A history of endometrial hyperplasia (see below).

- Epilepsy.

- Asthma.

- Otosclerosis.

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in cases where a contra-indication is discovered and in the following situations:

- Jaundice or deterioration in liver function.

- Significant increase in blood pressure.

- New onset of migraine-type headache.

- Pregnancy.

Endometrial hyperplasia:

The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen for at least 12 days of the cycle in non-hysterectomised women greatly reduces this risk.

Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Breast cancer:

A randomised placebo-controlled trial, the Women's Health Initiative study (WHI) and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestagen combinations or tibolone for HRT for several years (see Section 4.8).

For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Venous thromboembolism:

HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two-to threefold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

• Generally recognised risk factors for VTE include a personal or family history and severe obesity (BMI>30 kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

• Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

• The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the women is completely mobilised.

• If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnea).

Coronary artery disease (CAD):

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke:

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer:

Long-term (at least 5 to 10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long term use of combined HRT confers a different risk than estrogen-only products.

Other conditions:

• Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Duphaston is increased.

• Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

• Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex- hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

• There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

No interaction studies have been performed.

- The metabolism of progestagens may be increased by concomitant use of substances known to induce drug- metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (eg. Phenobarbital, phenytoin, carbamezapine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

- Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.

- Herbal preparations containing St John's Wort (Hypericum perforatum) may induce the metabolism of progestagens.

- Clinically an increased metabolism of progestagens may lead to decreased effect and changes in the uterine bleeding profile.

- Insulin and anti-diabetic requirements may change.

Pregnancy

Duphaston is not indicated during pregnancy. If pregnancy occurs during medication with Duphaston, treatment should be withdrawn immediately.

It is estimated that altogether 35 million women have been treated with dydrogesterone. Although the number of pregnancies is difficult to estimate, as an approximate it can be assumed that in utero foetuses were exposed to dydrogesterone in around 9 million pregnancies. From spontaneous surveillance system until now, there is no evidence that dydrogesterone can not be used during pregnancy. No other relevant epidemiological data on dydrogesterone are available.

However, a recent US case-contrile study investigating 502 cases with hypospadias and 1286 healthy controls suggested at least a 2-fold increased risk of second/third degree hypospadias among boys born by mothers who took progestogens (predominately progesterone) shortly prior or during pregnancy (OR 2.2, 95%CI 1.0-5.0). The casuality is unclear as the underlying disease itself for progesterone use in pregnancy may be potentially associated with a risk of hypospadias. For dydrogesterone, the risk of hypospadias is unknown.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal, or postnatal, development. Animal safety data are limited with respect to effects on parturition (see 5.3).

There is no evidence that dydrogesterone decreases fertility.

Lactation

Dydrogesterone is excreted in the milk of nursing mothers. A risk to the suckling child cannot be excluded. Dydrogesterone should not be used during breast-feeding.

Duphaston has no or negligible influence on the ability to drive and use machines.

Side effects include headaches, gastrointestinal upset, candidiasis, weight changes, fluid retention, and occasional hypertension.

When used in conjunction with an estrogen, the Undesirable effects relating to the particular estrogen used should also be considered, for example:

The undesirable effects reported in clinical trials and in post marketing experience following estrogen/progestagen therapy are:

Other adverse reactions obtained from the market with unknown frequency in association with dydrogesterone treatment:

-Increase in size of progestogen dependant neoplasms (e.g. meningioma) (see section 4.3).

Breast Cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For estrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trials are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

- For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

- For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be:

- For users of estrogen-only replacement therapy, between 0 and 3 (best estimate = 1.5) for 5 years' use, between 3 and 7 (best estimate = 5) for 10 years' use.

- For users of estrogen plus progestagen combined HRT, between 5 and 7 (best estimate = 6) for 5 years' use, between 18 and 20 (best estimate = 19) for 10 years' use.

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

- For 1000 women in the placebo group, about 16 cases of invasive breast cancer would be diagnosed in 5 years.

- For 1000 women who used estrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be between 0 and 9 (best estimate = 4) for 5 years' use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).'

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen users varies from 2-to 12-fold greater compared with non-users. Adding a progestagen to estrogen-only therapy greatly reduces this increased risk.

Other adverse reactions have been reported in association with estrogen/progestagen treatment:

- Estrogen-dependent neoplasma benign and malignant, e.g. endometrial cancer.

- Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use.

- Probable dementia (see section 4.4).

Limited data are available with regard to overdose in humans. Dydrogesterone was well tolerated after oral dosing (maximum daily dose taken to date in humans 360 mg). No reports of ill effects from overdose have been recorded. If a large overdose is discovered within two or three hours and treatment seems desirable, gastric lavage is recommended. There are no specific antidotes and treatment should be symptomatic.

Pharmacotherapeutic group: Genito Urinary system and sex hormones, ATC code: G03 DB01

Dydrogesterone

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

When used in conjunction with an estrogen, the pharmacodynamic properties relating to the particular estrogen used should also be considered, for example:

Clinical trial information:

- Relief of estrogen-deficiency symptoms and bleeding patterns.

- Relief of menopausal symptoms was achieved during the first few weeks of treatment.

- Regular withdrawal bleeding with Duphaston and Estradiol 1mg occurred in approximately 75-80% of women with a mean duration of 5 days. Withdrawal bleeding usually started on the day of the last pill of the progestagen phase. Break-through bleeding and/or spotting occurred in approximately 10% of the women; amenorrhoea (no bleeding or spotting) occurred in 10 - 25% of the women per cycle during the first year of treatment.

- With Duphaston and Estradiol 2mg, approximately 90% of women had regular withdrawal bleeding. The start day and duration of bleeding, and the number of women with intermittent bleeding was the same as with Duphaston and Estradiol 1mg, amenorrhoea occurred in 5 - 15% of the women per cycle during the first year of treatment.

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

In man, dydrogesterone is completely metabolised. The main metabolite of dydrogesterone is 20α-dihydrodydrogesterone (DHD) and is present in the urine predominantly as the glucoronic 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 absence of estrogenic and androgenic activity.

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

The dihydrodydrogesterone C_average is 13 ng/ml, the C_min is 4.1 ng/ml and the C_max is 63 ng/ml. The dydrogesterone C_average is 0.38 ng/ml the C_min is <0.1 ng/ml and the C_max is 2.5 ng/ml.

Dydrogesterone is not excreted in urine as pregnanediol, like progesterone. Analysis of endogenous progesterone production based on pregnanediol excretion therefore remains possible.

Receptor binding studies and functional activity studies revealed antiandrogenic potency of progesterone, dydrogesterone and its metabolite DHD is probably noticeably weaker than that of a progesterone. With regard to antiandrogenic effects mediated by inhibition of 5α-reductase type II, an important enzyme for differentiation of the male external genitalia, progesterone is as potent as the synthetic enzyme inhibitor finasteride, whereas dydrogesterone and DHD are inactive. The overall potential to act as antiandrogenic endocrine disruptors may be rated as highest for progesterone, lower for dydrogesterone and lowest for DHD.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal or postnatal development.

Limited animal safety data suggest that dydrogesterone has delaying effects on parturition, which is consistent with its progestogenic activity.

Lactose monohydrate

Starch (maize)

Magnesium Stearate

Hypromellose

Colloidal Anhydrous Silica

Macrogol 400

Titanium Dioxide (E171)

Purified Water

Not applicable.

5 years.

Do not store above 30˚C.

Keep the blister in the outer carton, in order to protect from moisture and light.

Cartons of 42 or 60 blister packed tablets in Al/PVC blister strips.

Not all pack sizes may be marketed.

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

Abbott Healthcare Products Limited

Mansbridge Road

West End

Southampton

SO18 3JD

United Kingdom

PA 108/10/1

Date of first authorisation: 28 January 1985

Date of last renewal: 27 January 2010

August 2011