Zuviston Tablets
Therapy Area
Women's Health
1.0 Generic name
Dydrogesterone Tablets IP 10 mg
2.0 Qualitative and quantitative composition
Each film coated tablet contains :
Dydrogesterone IP 10 mg
Colour : Titanium Dioxide IP
3.0 Dosage form and strength
Tablet 10 mg
4.0 Clinical particulars
4.1 Therapeutic indication
Progesterone deficiencies
- Treatment of dysmenorrhoea
- Treatment of endometriosis.
- Treatment of secondary amenorrhoea.
- Treatment of irregular cycles.
- Treatment of dysfunctional uterine bleeding.
- Treatment of pre-menstrual syndrome.
- Treatment of threatened abortion.
- Treatment of habitual abortion.
- Treatment of infertility due to luteal insufficiency.
- Luteal Support as a part of Assisted Reproductive Technology (ART) treatment.
Hormone replacement therapy
To counteract the effects of unopposed oestrogen on the endometrium in hormone replacement therapy for women with disorders due to natural or surgical induced menopause with an intact uterus.
4.2 Posology and method of administration
Dosages, treatment schedule and duration of treatment may be adapted to the severity of the dysfunction and the clinical response.
Dysmenorrhoea : 10 or 20 mg Dydrogesterone per day from day 5 to day 25 of the Menstrual cycle.
Dysfunctional uterine bleeding : When treatment is started to arrest a bleeding episode, 20 or 30 mg Dydrogesterone per day is to be given for up to 10 days. For continuous treatment, 10 or 20 mg Dydrogesterone per day should be given during the second half of the menstrual cycle. The starting day and the number of treatment days will depend on the individual cycle length.
Withdrawal bleeding occurs if the endometrium has been adequately primed with either endogenous or exogenous estrogen.
Secondary amenorrhoea : 10 or 20 mg Dydrogesterone per day, to be given daily for 14 days during the second half of the theoretical menstrual cycle to produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen.
Pre-menstrual syndrome : 10 mg Dydrogesterone twice daily starting with the secondhalf 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 : 10 or 20 mg Dydrogesterone per day 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.
Threatened abortion : An initial dose of up to 40 mg Dydrogesterone may be given followed by 20 or 30 mg per day until symptoms remit
Habitual abortion : 10 mg Dydrogesterone twice daily until the twentieth week of pregnancy.
Infertility due to luteal insufficiency : 10 or 20 mg Dydrogesterone daily starting with the second half of the menstrual cycle until the first day of the next cycle. Treatment should be maintained for at least three consecutive cycles.
Hormone replacement therapy :
- Continuous sequential therapy : An estrogen is dosed continuously and one tablet of 10 mg Dydrogesterone is added for the last 14 days of every 28 day cycle, in a sequential manner.
- Cyclic therapy : When an estrogen is dosed cyclically with a treatment-free interval, usually 21 days on and 7 days off. One tablet of 10 mg Dydrogesterone is added for the last 12 -14 days of estrogen therapy.
- Depending on the clinical response, the dosage can subsequently be adjusted to 20 mg Dydrogesterone per day.
There is no relevant use of Dydrogesterone before menarche. The safety and efficacy of Dydrogesterone in adolescents aged 12-18 years has not been established. Currently available data are described in 'Adverse Reactions and 'Pharmacodynamic Properties', but no recommendation on a posology can be made.
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients.
- Known or suspected progestogen dependent neoplasms (e.g. meningioma)
- Undiagnosed vaginal bleeding.
- If used to prevent endometrial hyperplasia (in women using estrogens) : Contraindications for use of oestrogens in combination with progestagens, such as Dydrogesterone.
4.4 Special warnings and precautions for use
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 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.
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 Dydrogesterone and ceasing the treatment should be considered :
Porphyria
Depression
Abnormal liver function values caused by acute or chronic liver disease
Other conditions
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucosegalactose 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, however, the balance of benefits and risks for these women may be more favourable than in older women.
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 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.
Endometrial hyperplasia
Long-term use of oestrogens without addition of progestagens increases the change of endometrial hyperplasia and endometrial carcinoma in women with a uterus. This risk may largely be prevented by combining the oestrogen therapy for at least 12 days per cycle with a progestagen, such as Dydrogesterone.
Breast cancer
The overall evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestogen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT. The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment. HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the 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 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 a similar, or slightly smaller, risk.
Venous thrombo-embolism
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 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 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).
Coronary artery disease (CAD)
There is no evidence from randomized controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogenprogestogen 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.
Cerebrovascular accident (CVA)
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 agedependent, the overall risk of stroke in women who use HRT will increase with age.
4.5 Drugs interactions
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 (Hypericumperforatum), 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.
4.6 Use in special populations
Pregnancy
It is estimated that more than 9 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. Dydrogesterone can be used during pregnancy if clearly indicated.
Breast feeding
No data exist 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.
Fertility
There is no evidence that Dydrogesterone decreases fertility at therapeutic dose.
4.7 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.
4.8 Undesirable effects
Organ class according to MedDRA database | Common ≥1:100, <1:10 | Uncommon ≥1:1,000, <1:100 | Rare ≥1:10,000, <1:1,000 |
Neoplasms, benign, Malignant and nonspecified (including cysts and polyps) | Growth of progestogendepen dent neoplasms (e.g. Eningioma)* | ||
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 | |
Hepatobiliary disorders | Disturbed liver function (with Icterus, Asthenia or Malaise, and abdominal pain | ||
Skin and subcutaneous tissue disorders pruritus, Urticaria) | Allergic dermatitis (e.g. rash, | Angiooedema* | |
Reproductive system and breast disorders | Disturbed menstruation (including Metrorrhagia, menorrhagia, Oligo- /amenorrhoea, Dysmenorrhoea and Irregular menstruation) Painful/ sensitive breasts | Swelling of the breasts | |
General disorders and administration site conditions | Oedema | ||
Investigations | Weight gain |
* Adverse effects reported spontaneously
Undesirable effects that are associated with an estrogen-progestogen treatment (see also 'Warnings and Precautions' and the product information of the estrogen preparation) :
Breast cancer, Endometrial hyperplasia, Endometrial carcinoma, Ovarian cancer
Venous thromboembolism
Myocardial infarction, Coronary artery disease, Ischemic stroke
Reporting of suspected adverse reactions
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 e-mail to : medico@zuventus.com
Website : https://www.zuventus.com/drug-safety-reporting By reporting side effects, you can help provide more information on the safety of this medicine.
4.9 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.
5.0 Pharmacological properties
5.1 Mechanism of action
Dydrogesterone is an orally-active progestogen which produces a complete secretory endometrium in an estrogen-primed uterus thereby providing protection against the increased risk for endometrium hyperplasia and/or carcinogenesis induced by estrogens. It is indicated in all cases of endogenous progesterone deficiency.
5.2 Pharmacodynamic properties
Dydrogesterone has no estrogenic, no androgenic, no thermogenic, no anabolic and no corticoid activity. Dydrogesterone does not suppress ovulation.
5.3 Pharmacokinetic properties
Absorption
After oral administration Dydrogesterone is rapidly absorbed with a Tmax of between 0.5 and 2.5 hours. The absolute biological availability of Dydrogesterone (20 mg oral dose versus 7.8 mg intravenous infusion) is 28%. The following tables gives the pharmacokinetic parameters of Dydrogesterone (D) and 20α Dihydrodydrogesterone (DHD) after administration of a single dose of 10 mg Dydrogesterone :

Distribution
After intravenous administration of Dydrogesterone the steady-state distribution volume is around 1400 l. More than 90% of Dydrogesterone and DHD are bound to plasma-proteins.
Metabolism
After oral administration Dydrogesterone is quickly metabolised to DHD. The plasma levels of the main active metabolite DHD show a peak around 1.5 hours after administering the dose. The plasma levels of DHD are substantially higher than the related medicinal product. The AUC and Cmax ratios of DHD and Dydrogesterone are of the order of magnitude of respectively 40 and 25. The mean terminal half-life of Dydrogesterone and DHD varies from respectively 5 to 7 and 14 to 17 hours. A common characteristic of all characterised metabolites is the retention of the 4,6-diene-2-one configuration of the original product and the absence of 17α hydroxylation. This explains the absence of oestrogenic and androgenic effects of Dydrogesterone.
Elimination
After oral administration of labelled Dydrogesterone on average 63% of the dose is excreted in the urine. The total plasma clearance is 6.4 l/minute. Within 72 hours the excretion is complete, DHD is present in the urine mainly as the conjugated glucuronic acid.
6.0 Nonclinical properties
6.1 Animal toxicology or pharmacology
Non-clinical data obtained during conventional investigation into the toxixcity of single and repeated doses, genotoxicity and the carcinogenic potential do not show any special risks for humans. Research into the toxic effects on the reproduction of rats shows for high doses (> 80 times the human exposure) an increased incidence of erect nipples (during days 11-19 of the lactation period) and of hypospadia in male rats. The clinical relevance of these observations is not known. The limited data on safety in animals indicate that Dydrogesterone has an extending effect on delivery, which corresponds with the progestogenic action.
7.0 Description
Dydrogesterone is a synthetic progesterone with an oral biological availability that causes a secretory phase of the endometrium in a uterus prepared by oestrogen. It gives protection against the increased risk of endometrial hyperplasia and/or endometrial carcinoma that is induced by oestrogens.
8.0 Pharmaceutical particulars
8.1 Incompatibilities
Not applicable
8.2 Shelf-life
Refer on the pack.
8.3 Packaging information
PVC/PVDC-Alu blister pack of 10 tablets.
8.4 Storage and handing instructions
Store at temperature not exceeding 25°C. Protect from light
Keep out of reach of children.
9.0 Patient counselling information
Ask the patient to report any adverse events.
Ask the patients if Porphyria, Depression, Abnormal liver function values caused by acute or chronic liver disease is present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment.
Patients should be asked to exercise caution when driving and operating machinery
Ask the patient to report if breakthrough bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued.
12.0 Date of revision
31 May 2022