Source: Υπουργείο Υγείας (CY) Revision Year: 2025 Publisher: Theramex Ireland Limited, 3rd Floor, Kilmore House, Park Lane, Spencer Dock, Dublin 1, D01 YE64, Ireland
Before initiating dydrogesterone treatment for abnormal bleeding the etiology for the bleeding should be clarified. Breakthrough bleeding and spotting may occur during the first months of the treatment. If breakthrough 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.
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 dydrogeserone and ceasing the treatment should be considered:
Meningioma:
The occurrence of meningiomas (single and multiple) has been reported in association with use of dydrogesterone. Patients should be monitored for signs and symptoms of meningiomas in accordance with clinical practice. If a patient is diagnosed with meningioma, any dydrogesterone containing treatment must be stopped (see section 4.3). Tumour shrinkage has been observed after treatment discontinuation.
The following warnings and precautions apply when using dydrogesterone in combination with estrogens for hormone replacement therapy (HRT):
See also the warnings and precautions in the product information of the estrogen preparation.
For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect the quality of life. In all cases, careful appraisal of the risks and benefits should be undertaken at least annually and HRT should be only continued as long as the benefit outweighs the risk.
Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.
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 appropriate imaging tools, e.g., mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods.
The addition of a progestogen such as dydrogesterone cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestogen therapy in nonhysterectomized women can prevent the excess risk associated with estrogen-only HRT.
The overall evidence shows an increased risk of breast cancer in women taking combined estrogen-progestogen or estrogen-only HR, that is dependent on the duration of taking HRT.
Combined estrogen-progestogen therapy: The randomized placebo-controlled trial, Women's Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestogen for HRT that becomes apparent after about 3 (1-4) years. Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more. HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-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.
HRT is associated with a 1.3-3 fold risk of developing venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later.
Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients.
Generally recognized risk factors for VTE include, use of estrogens, older age, major surgery, prolonged immobilization, obesity (BMI >30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE.
As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilization is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilized.
In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counseling regarding its limitations (only a proportion of thrombophilic defects are identified by screening).
If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g., antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.
Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.
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).
There is no evidence from randomized controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestogen or estrogen-only HRT.
Combined estrogen-progestogen therapy: The relative risk of CAD during use of combined estrogenprogestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to estrogen-progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.
Combined estrogen-progestogen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age.
This medicinal product contains Lactose monohydrate.
Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
In vitro data show that the major metabolic pathway generating the main pharmacologically active metabolite 20α dihydrodydrogesterone (DHD) is catalyzed by aldo-keto reductase 1C (AKR 1C) in human cytosol. Next to the cytosolic metabolism there are metabolic transformations by cytochrome P450 iso-enzymes (CYPs), nearly exclusively via CYP3A4, resulting in several minor metabolites. The main active metabolite DHD is substrate for metabolic transformation by CYP3A4.
Therefore, the metabolism of dydrogesterone and DHD may be increased by concomitant use of substances known to induce CYP enzymes such as anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine), anti-infectives (e.g., rifampicin, rifabutin, nevirapine, efavirenz) and herbal preparations containing e.g. St John's Wort (Hypericum perforatum), sage, or gingko biloba. Ritonavir and nelfinavir, although known as strong cytochrome enzyme inhibitors, by contrast exhibit enzyme-inducing properties when used concomitantly with steroid hormones.
Clinically, an increased metabolism of dydrogesterone may lead to a decreased effect.
In vitro studies have shown that dydrogesterone and DHD do not inhibit or induce CYP drug metabolizing enzymes at clinically relevant concentrations.
It is estimated that more than 10 million pregnancies have been exposed to dydrogesterone. So far there were no indications of a harmful effect of dydrogesterone use during pregnancy.
Some progestogens have been reported in the literature to be associated with an increased risk of hypospadias. However due to confounding factors during pregnancy, no definitive conclusion can be drawn regarding the contribution of progestogens to hypospadias. Clinical studies, where a limited number of women were treated with dydrogesterone early in pregnancy, have not shown any increase in risk. No other epidemiological data are hitherto available.
Effects in non-clinical embryo-fetal and post-natal development studies were in line with the pharmacological profile. Untoward effects occurred only at exposures which exceeded the maximum human exposure considerably, indicating little relevance to clinical use (see section 5.3).
Dydrogesterone can be used during pregnancy if clearly indicated.
No data exists on excretion of dydrogesterone in mother's milk. Experience with other progestogens indicates that progestogens and the metabolites pass to mother's milk in small quantities. Whether there is a risk to the child is not known. Therefore, dydrogesterone should not be used during the lactation period.
There is no evidence that dydrogesterone decreases fertility at therapeutic doses.
Dydrogesterone has minor influence on the ability to drive and use machines. Infrequently, dydrogesterone may cause somnolence and/or dizziness, especially within the first few hours after intake. Therefore, care should be taken when driving or using machines.
The undesirable effects reported in clinical trials and/or in post marketing experience following dydrogesterone therapy are:
| MedDRA system organ class | Common ≥1/100, <1/10 | Uncommon ≥1/1,000, <1/100 | Rare ≥1/10,000, <1/1,000 |
| Neoplasms benign, malignant and unspecified (incl. cysts and polyps) | Increase in size of progestogen dependent neoplasms* (e.g. meningioma) | ||
| Blood and the lymphatic system disorders | Haemolytic anaemia* | ||
| Psychiatric disorders | Depressed mood | ||
| Immune system disorders | Hypersensitivity | ||
| Nervous system disorders | Migraines/ headache | Dizziness | Somnolence |
| Hepatobiliary disorders | Hepatic function abnormal (with Asthenia or Malaise, and Abdominal pain) | ||
| Skin and subcutaneous tissue disorders | Dermatitis allergic (e.g. rash, pruritus, urticaria) | Angioedema* | |
| Reproductive system and breast disorders | Menstrual disorders (including metrorhagia, menorrhagia, oligo/amenorrhoea and irregular menstruation) Breast pain/tenderness | Breast swelling | |
| General disorders and administration site conditions | Oedema | ||
| Investigations | Weight increased |
* Undesirable effects from spontaneous reporting which have not been observed in clinical trials have been attributed to the frequency 'rare' based on the fact that the upper limit of the 95% confidence interval of the frequency estimate is not higher than 3/x where x =3483 (total number of subjects observed in clinical trials).
Undesirable effects in adolescent population:
Based on spontaneous reports and limited clinical trial data, the adverse reaction profile in adolescents is expected to be similar to that seen in adults.
Undesirable effects that are associated with an estrogen-progestogen treatment (see also section 4.4 and the product information of the estrogen preparation):
Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported to Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Tel: +357 22608607, Fax: +357 22608669, Website: www.moh.gov.cy/phs.
Not applicable.
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