Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Mylan IRE Healthcare Limited, Unit 35/36, Grange Parade, Baldoyle Industrial Estate, Dublin 13, Ireland
Before initiating dydrogesterone treatment for abnormal bleeding the etiology for the bleeding should be clarified.
Treatment with dydrogesterone has infrequently 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.
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.
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 dydrogesterone and ceasing the treatment should be considered:
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 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.
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, 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 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 non-hysterectomised 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 HRT, that is dependent on the duration of taking HRT.
Combined estrogen-progestogen therapy: The randomised 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 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 HRT’s 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 recognised risk factors for VTE include: use of estrogens, older age, major surgery, prolonged immobilisation, 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 immobilisation 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 mobilised. 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 counselling 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 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 randomised 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 estrogen-progestogen 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, 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 progestogens and DHD may be increased by concomitant use of substances known to induce CYP enzymes, such as anticonvulsants (eg. phenobarbital, phenytoin, carbamezapine), 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 inhibitors, by contrast exhibit enzyme-inducing properties when used concomitantly with steroid hormones.
Clinically an increased metabolism of dydrogesterone may lead to decreased effect.
In vitro studies have shown that Dydrogesterone and DHD do not inhibit or induce CYP drug-metabolising 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.
Duphaston has a minor influence on the ability to drive and use machines.
Infrequently, dydrogesterone may cause mild somnolence and/or dizziness, especially within the first few hours after intake.
Therefore, care should be taken when driving or using machines.
The most commonly reported adverse drug reactions of patients treated with dydrogesterone in clinical trials of indications without estrogen treatment are migraines/headache, nausea, menstrual disorders and breast pain/tenderness. The following undesirable effects have been observed with the frequencies indicated below during clinical trials using dydrogesterone (n=3483) in indications without estrogen treatment and from spontaneous reporting:
| 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 lymphatic system disorders | Haemolytic anaemia* | ||
| Immune system disorders | Hypersensitivity | ||
| Psychiatric disorders | Depressed mood | ||
| Nervous system disorders | Headache, Migraine | Dizziness | Somnolence |
| Gastrointestinal disorders | Nausea | Vomiting | |
| Hepatobiliary disorders | Hepatic function abnormal, (with Asthenia or Malaise, Jaundice and Abdominal pain) | ||
| Skin and subcutaneous tissue disorders | Dermatitis allergic,(e.g. Rash, Urticaria, Pruritus) | Angioedema* | |
| Reproductive system and breast disorders | Menstrual disorders (including metrorhagia, menorrhagia, oligo-/amenorrhoea, dysmenorrhoea and irregular menstruation) Breast pain/tenderness | Breast swelling | |
| Congenital and familial/genetic disorders | Aggravation of porphyria* | ||
| General disorders and administration site reactions | 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).
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.
Other adverse reactions have been reported in association with estrogen/progestogen treatment (see section 4.4 and the product information of the estrogen preparation):
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 HPRA Pharmacovigilance, Website: www.hpra.ie
Not applicable.
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