Health is our business

Duphaston

Infertility

Duphaston

Duphaston

10 mg Dydrogesteron

Film-coated tablet

Read this entire leaflet carefully before you start taking this medicine.

Keep this leaflet. You may need to read it again. If you have questions not answered by this pamphlet, please ask your doctor or pharmacist. This medicine has been prescribed to you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours.

 

Duphaston is a round, biconvex, scored, white coloured film-coated tablet for oral administration bearing the inscription ‘155’ on either side of the break mark on one side of the tablet. Each tablet contains 10 mg of dydrogestrone.

The score line is present only to facilitate breaking the tablet into two halves for ease of use and swallowing and is not intended to divide the tablet into two equal doses.

Excipients (nonmedical ingredients):

Tablet core: Lactose monohydrate, hypromellose, maize starch, colloidal anhydrous silica, magnesium stearate.

Film-Coating: Hypromellose, macrogol 400, titanium dioxide (E171)

Posology

Always take Duphaston exactly as your doctor has prescribed. If you have any questions, contact your doctor or pharmacist.

If you forget to take your tablet(s), do not take a double dose to compensate for it. If you require further information, please ask your doctor or pharmacist for advice.

The following dosage regimens are recommended for treatment with Duphaston 10.

The quantities can be adjusted according to the seriousness of the disorder to be treated and the individual patients’ responses to the treatment.

Posology for specific indications:

Dysmenorrhea:

Take one tablet twice daily from day 5 to day 25 of the cycle.

Dosages of 10 mg several times a day should be spread over the day. It is recommended that treatment should start at the highest dose

 

Endometriosis:

Take one tablet two or three times daily from day 5 to day 25 of the cycle or continuously (as prescribed by your doctor). Dosages of 10 mg several times a day should be spread over the day. It is recommended that treatment should start at the highest dose.

 

Dysfunctional bleeding (to stop bleeding)

Take one tablet twice daily for five to seven days. The blood loss is reduced considerably within a few days. A few days after the end of this treatment, a heavy withdrawal bleed occurs and the patient should be warned about this.

 

Dysfunctional bleeding (To prevent bleeding):

Take one tablet daily from day 11 to day 25 of the cycle, if necessary combined with an estrogen for 2 to 3 cycles. After this the treatment can be discontinued, in order to check that the patient has a normal cycle again.

Withdrawal bleeding occurs if the endometrium has been adequately primed with either endogenous or exogenous estrogen.

 

Amenorrhea (cessation of menstruation)

1 or 2 tablets of Duphaston 10 per day from the 11th to the 25th day of the cycle to give optimum secretion transformation of the endometrium, that is adequately prepared with an endogenous or exogenous estrogen.

 

Premenstrual syndrome:

Take one tablet twice daily starting with the second half of the menstrual cycle until the first day of the next cycle. The starting day and the number of treatment days will depend on the individual cycle length.

 

Irregular cycles:

Take one tablet twice daily from day 11 to day 25 of the cycle. The starting day and the number of treatment days will depend on the individual cycle length.

 

Threatened abortion:

Take four tablets at once, then one tablet every eight hours until symptoms abate. Dosages of 10 mg several times a day should be spread over the day. It is recommended that treatment should start at the highest dose.

 

Habitual abortion:

Take one tablet twice daily until the twentieth week of pregnancy; the dose can then be gradually reduced. Treatment should preferably be started before conception.

If the symptoms of threatened abortion occur during treatment, treatment should be continued as described for that indication.

 

Infertility due to luteal insufficiency:

Take one tablet daily from day 14 to 25 of the cycle. Continue the treatment for at least six consecutive cycles. In addition, it is advisable to continue treatment for the first few months of pregnancy as described under 'Habitual abortion’. If you are uncertain about how long to continue the treatment, talk to your doctor. Duphaston is not recommended for use in children below age 18 due to insufficient data on safety and efficacy.

 

For Hormone Replacement therapy:

Prevention of hyperplasia of the endometrium in the post menopause

For each cycle of 28 days’ estrogen therapy for the first 14 days’ estrogen only is used and for the following 14 days in addition to estrogen therapy once a day 1 or 2 tablets of dydrogesterone 10 mg are taken. With a dose of 2 tablets of dydrogesterone 10 mg per day the tablets must be taken in divided doses over the day. Withdrawal bleeding usually occurs while taking dydrogesterone.

Use of combined estrogen/progesterone therapy in postmenopausal women should be limited to the lowest effective dose and the shortest time compatible with the treatment aims and risks for the individual woman and must be regularly assessed.

There is no relevant use of dydrogesterone before the menarche. The safety and efficacy of dydrogesterone in adolescents aged from 12 to 18 years has not been established.

Luteal support as part of an Assisted Reproductive Technology (ART)n treatment

1 tablet of Duphaston 10 three times a day (30 mg daily) starting at the day of oocyte retrieval and continuing for 10 weeks if pregnancy is confirmed.

Method of administration for oral use.

For administration of higher doses, the tablets should be taken in divided doses over the day.

.

Contraindications

  • Vaginal bleeding, where the cause has not been established.
  • Treatment for luteal support as part of an Assisted Reproductive Technology (ART) treatment should be discontinued upon diagnosis of abortion or miscarriage.
  • Presence of serious liver disorders, or serious liver disorders in the medical history until the liver function values have returned to normal.
  • Contraindications for use of estrogens in combination with progestogens such as dydrogesterone in combined therapy.
  • Hypersensivity to the active ingredients or to any other excipients listed in the “Excipients”
  • Known or suspected sex hormone dependent malignancies.

Special warnings and precautions for use

Before starting treatment with dydrogesterone because of dysfunctional uterine bleeding an organic cause should be excluded.

Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding and spotting continue to occur when treatment has already been underway for some time, or continue when treatment is discontinued, the cause of this should be ascertained, if necessary by taking an endometrial biopsy to exclude malignancy of the endometrium.

If one of the following disorders occurs during use for the first time or gets worse, stopping the treatment should be considered.

  • exceptionally severe headache, migraine or symptoms that may indicate cerebral ischemia.
  • marked increase in blood pressure.
  • occurrence of venous thromboembolism.

In cases of habitual or threatened miscarriage, the viability of the fetus should be ascertained, and it is necessary to monitor during treatment whether the pregnancy is still progressing and whether the embryo is still alive.

Conditions for which monitoring is necessary:

It is known that the following rarely occurring conditions may be affected by sex hormones and may arise or get worse during pregnancy or during the use of sex hormones: cholesteric icterus, herpes gestations, severe pruritus, otosclerosis and porphyria.

Patients with a history of depression must be carefully monitored; if severe depression recurs, treatment with dydrogesterone must be stopped.

Other conditions

Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency or glucose- galactose malabsorption should not use this medicinal product.

Warnings and precautions regarding the use of Duphaston in the indication “to prevent endometrial hyperplasia in the postmenopausal period

N.B. See also the warnings in the product information for the estrogen preparation

To treat postmenopausal symptoms, treatment with hormone replacement therapy (HRT) should only be started if these symptoms have an adverse effect on quality of life. The benefits and disadvantages of HRT should be carefully assessed in any case at least once a year, and the treatment should only be continued if the benefits outweigh the disadvantages

Medical examination/ follow-up

Before hormone replacement therapy (HRT) is started or when it is resumed after a break, a full medical history (including family medical history) must be taken. A physical examination (including a gynecological and breast examination) must be carried out on the basis of the medical history, the contraindications and the warnings. Regular checks are recommended during treatment, at a frequency and of a type adapted to the individual. Women must be told what changes in their breasts they must consult their doctor about (see paragraph “Breast cancer” below).

Examination of the breasts, including imaging such as mammography, must be carried out in accordance with the current guidelines for screening, taking into account the medical situation of the individual woman.

Endometrial hyperplasia and carcinoma

Long-term use of estrogens without progestogen supplement increases the risk of endometrial hyperplasia and endometrial carcinoma in women with a uterus. Depending on the duration and estrogen dose the risk may be 2 to 12 times higher than in women who do not use estrogen. After stopping estrogen treatment this risk continues to exist for at least 10 years. This extra risk can be prevented by combining the estrogen therapy with a progestogen such as dydrogesterone for at least 12 days per month/28-day cycle.

Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting occur after considerable time on treatment or continue when treatment is discontinued, further investigation is indicated. This may mean taking an endometrial biopsy to exclude malignancy.

Breast cancer

All the available data indicate an increased risk of breast cancer if women take a combination of estrogen and progestogen as HRT and possibly even if they take estrogen-only as HRT. This risk depends on the duration of use.

Combined treatment with estrogen and progestogens:

A randomized, placebo-controlled study (Women’s Health Initiative Study (WHI)) and epidemiological studies have consistently shown that there is an increased risk of breast cancer after using for 3 years or longer. After discontinuing treatment this extra risk continues to exist for a maximum of 5 years. As a result of treatment with HRT, in particular combined estrogen-progestogen treatment, the density of the mammography images increases, which may adversely affect the radiographic detection of breast cancer

Ovarian cancer:

Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies, including the WHI trial, suggest that use of combined HRTs may be associated with a similar, or slightly smaller risk.

Venous thromboembolisms:

Hormone replacement therapy is accompanied by a 1.3-3 times higher risk of a venous thromboembolism (VTE) occurring, i.e. of deep-vein thrombosis or pulmonary embolism. The chance of this occurring is greater during the first year of HRT treatment than thereafter.

Patients with known thrombophilia have an increased risk of developing VTE and HRT could further increase that risk. HRT is therefore contraindicated in these patients.

Generally recognized risk factors for the occurrence of VTE are the use of estrogens, greater age, major surgery, long-term immobilization, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus regarding the possible role of varicose veins in the occurrence of VTE. In all post-operative patients, consideration should be given to taking measures after surgery to prevent VTE. If long-term immobilization will occur after elective surgery it is recommended that HRT be discontinued 4-6 weeks beforehand. The treatment may only be resumed when the woman is fully mobile once again.

Women who themselves have no history of VTE but who have a first degree relative who has had thrombosis at a young age can be offered screening after the limitations of this have been clearly discussed (only a certain number of thrombophilia abnormalities can be determined by screening). If a thrombophilia deviation is found which has led to thrombosis in family members or if it relates to a serious abnormality (e.g. ant thrombin, protein S or protein C deficiency, or a combination of defects) HRT is contraindicated.

In women who are already receiving anticoagulant therapy, the benefits and risks of HRT should be carefully assessed.

If a VTE develops after treatment has been started, administration of the medication should be discontinued. Patients must be informed that they should contact their doctor immediately if they experience symptoms that could be the result of thromboembolism (for example, painful swelling of a leg, sudden pain in the chest, shortness of breath).

Coronary Herat Disease(CHD):

Randomized controlled studies have produced no evidence that women with or without existing CHD who received HRT with estrogen in combination with progestogen or estrogen-only were protected against myocardial infarction.

Combined treatment with estrogen and progestogens:

The relative risk of the occurrence of CHD during HRT with a combination of estrogen and progestogen is slightly increased. Since the baseline absolute risk of the occurrence of CHD is greatly dependent on age, the number of extra cases of CHD as a result of the use of estrogen-progestogen in women approaching menopause is very low, but that does increase as they get older.

Ischemic (CVA)

Use of combined HRT or HRT with estrogen-only is accompanied by a 1 to 1.5 times higher risk of ischaemic CVA. The relative risk does not change with ageing or with the time that has elapsed since the menopause. However, because the basic risk of CVA is highly dependent on age, the absolute risk will increase with ageing.

Excipients

  This medicinal product contains lactose monohydrate.

Patients with rare hereditary conditions, such as galactose intolerance, Lapp-lactase deficiency or glucose- galactose malabsorption should not take this medicinal product.

Interaction with other medicinal products and other forms of reactions

In vitro data that the main active metabolite 20α-dihydrodydrogesterone (DHD) and to less extent also dydrogesterone are primarily metabolized by CYP3A4.

Substances that increase the clearance of progestogens (less efficacy due to enzyme induction) are for example: barbiturates, phenytoin, carbamazepine, primidone, rifampicin and HIV medication like ritonavir, neviparine and efavirenz, and possibly also products containing the herb St. John’s Worth (hypericum perforatum).

An increase in the clearance of dydrogesterone may lead to a clinical decrease of effect and changes in the bleeding pattern.

Substances with variable effects on the clearance of progestogens:

Many combinations of HIV protease inhibitors and non-nucleoside reverse-transcriptase inhibitors, including combinations with HCV inhibitors could, if concomitantly administered with progestogens, raise or lower the plasma concentrations of the progestogen. In some cases, the net effect of these changes could be clinically relevant.

For this reason, the product information of HIV/HCV medicines should be consulted, if they are administered concomitantly, to determine potential interactions and any associated recommendations.

Substances that decrease clearance of progestogens (enzyme inhibitors):

The clinical relevance of possible interactions with enzyme inhibitors is unknown. Concomitant use of strong CYP3A4 inhibitors may raise the plasma concentrations of progestogens.

Fertility, Pregnancy and lactation

 

Pregnancy

It is estimated that over 9 million women have already been exposed to dydrogesterone during pregnancy. To date there were no indications that the use of dydrogesterone during pregnancy has a harmful effect. In the literature a study is described in which it was found that the use of some progestogens can be accompanied by an increase in the risk of hypospadia occurring. However, because this has not been clearly confirmed to date in other studies, no final conclusion can be drawn about the effect of progestogens on the occurrence of hypospadia.

Clinical trials in which a limited number of women were treated with dydrogesterone in the first stage of pregnancy did not show that the risk is increased. To date no other epidemiological data are available.

The effects that were observed during non-clinical study into embryo-foetal and postnatal development corresponded with the pharmacological profile. Unwanted effects only occurred in case of exposure that was considerably higher than the maximum exposure in humans.

Dydrogesterone may be administered during pregnancy if there is a clear indication for this. Lactation

It is not known whether dydrogesterone is excreted in breast milk. No research has been done into the excretion of dydrogesterone in breast milk. Experiences with other progestogens indicate that progestogens and their metabolites are found in small quantities in breast milk. It is not known whether there is a risk for the child. Dydrogesterone should therefore not be used while breastfeeding.

Fertility

There are no data on the effect of dydrogesterone on fertility.

Effects on ability to drive and use machines

Dydrogesterone has a slight effect on ability to drive and to use machinery.

In rare cases dydrogesterone may cause somnolence and/or dizziness, in particular during the first couple of hours after taking it. Caution is therefore advised when driving and operating machinery.

Undesirable effects

The adverse effects of this product most commonly reported in patients who were treated with Dydrogesterone during clinical trials into indications without estrogen treatment were vaginal hemorrhage metrorrhagia, painful/ sensitive breasts nausea, vomiting, abdominal pain and migraine/headache.

 

Organ class according to MedDRA database

Very common

≥1/10

Common

≥1/100, <1/10

Uncommon

≥1/1,000,

<1/100

Rare

≥1/10,000, <1/1,000

Neoplasms, benign, malignant and non-specified (including cysts and polyps)

 

 

 

Growth of progestogen- dependent neoplasms (e.g. meningioma)*

Blood and lymphatic system disorders

 

 

 

Haemolytic anaemia*

Psychiatric        disorders

 

 

Depression

 

Immune system disorders

 

 

 

Hypersensitivity

Nervous system disorders

 

Migraine/ headache

Dizziness

Somnolence

Gastrointestinal disorders

 

Nausea, vomiting, abdominal pain

 

 

Hepatobiliary disorders

 

 

Disturbed liver function (with icterus, asthenia or malaise, and abdominal pain)

 

Skin and subcutaneous tissue disorders

 

 

Allergic dermatitis (e.g. rash, pruritus, urticaria)

               

Angioedema*

Reproductive system and breast disorders

Vaginal hemorrhage

Disturbed menstruation (including metrorrhagia, menorrhagia, oligo-

/amenorrhoea

,

dysmenorrhoe a and irregular menstruation) Painful/ sensitive breasts

 

Swelling of the breasts

General disorders and administration site conditions

 

 

 

Edema

Investigations

 

 

Weight gain

 

 

 

 

* Adverse effects reported spontaneously but not observed during clinical trials are classified as “rare” in view of the fact that the upper limit of the 95% confidence interval of the estimated frequency is not higher than 3/x, where x=3,483 (the total number of patients in the clinical trials).

Adverse effects that may occur during treatment with estrogen-progestogen (see also Special warnings and precautions for use and the product information for the estrogen formulation):

  • Breast cancer, endometrial hyperplasia, endometrial carcinoma, ovarian cancer
  • Ovarian cancer: use of estrogen-only or combined estrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed. A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2,000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2,000 will be diagnosed with ovarian cancer over a 5-year period.
  • Venous thromboembolism
  • Myocardial infarction, coronary heart disease, ischemic CVA Report of suspected adverse reactions

If you get any side effects, talk you your doctor or pharmacist. By reporting side affects you can help provide more information on the safety on this medicine.

Overdose

Symptoms

Dydrogesterone is a substance with very low toxicity. Nausea, vomiting, lethargy and dizziness are symptoms which may theoretically occur in the event of an overdose. There are no known cases in which an overdose of dydrogesterone led to harmful effects.

Treatment

Specific treatment is clearly not necessary. In case of overdose symptomatic treatment may be considered.

Shelf life and storage conditions

5 years.

Do not store above 30˚ C.

Keep the blister in the outer carton, in order to protect from moisture. Do not use the medicine after the expiry date stated on the carton. Keep this medicine out of the sight and reach of children.

Pack sizes

10, 14 or 20 film-coated tablets per pack (not all pack sizes may be marketed).

The blisters are made of aluminum foil and PVC film, uncoated or coated with PVDC.

Further information

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

The information in this leaflet is limited. For further information, please contact your doctor or pharmacist.

Date of information 27 November 2019 Manufactured by Abbott Biologicals B.V., The Netherlands

For:

Abbott Healthcare Products B.V., The Netherlands