Dydrogest

White colour, round shaped, biconvex film-coated tablets plain on both sides.
Each Film-Coated tablet contains: Dydrogesterone 10 mg.
Excipients/Inactive Ingredients: q.s.

Progestogen (Pregnadien derivative).
Pharmacology: Pharmacokinetics: 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%.
Distribution: After intravenous administration of Dydrogesterone the steady-state distribution volume is around 1400 L. More than 90% of Dydrogesterone and 20α-dihydrodydrogesterone (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 characterized metabolite is the retention of the 4, 6-diene-3-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 labeled 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.
Dependence of dose and time: The pharmacokinetics of single and multiple doses are linear in the oral dosage range from 2.5 to 10 mg. Comparison of the kinetics of single and multiple doses shows that the pharmacokinetics of Dydrogesterone and DHD do not change as a result of repeated dosing. Steady state is reached after 3 days of treatment.

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

Dosages, treatment schedule and duration of treatment may be adapted to the severity of the dysfunction and the clinical response.
Dysfunctional uterine bleeding: When treatment is started to arrest a bleeding episode 10 mg b.i.d. (twice a day) for (5) five to (7) seven days.
For continuous treatment, 10 mg twice a day from day 11 to day 25 of the cycle.
Withdrawal bleeding occurs if the endometrium has been adequately primed with either endogenous or exogenous estrogen.
Secondary amenorrhoea: 10 mg b.i.d. (twice a day) from day 11 to 25 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 b.i.d. (twice a day) from day 12 to 26 of the cycle. The dosage may be increased if necessary.
Endometriosis: 10 mg b.i.d. (twice a day) times daily from day 5 to 25 of the cycle, or continuously.
Dysmenorrhoea: 10 mg b.i.d. (twice a day) from day 5 to 25 of the cycle.
Irregular cycles: 10 mg twice a day from day 11 to 25 of the cycle.
Infertility due to luteal insufficiency: 10 mg b.i.d. (twice a day) from day 11 to 25 of the cycle. Treatment should be maintained for at least three consecutive cycles.
Hormone replacement therapy: The standard dose is 10 mg daily for the 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.
Method of administration: Oral.

Vaginal bleeding, where the cause has not been established.
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 oestrogens in combination with progestogens such as Dydrogesterone in combined therapy.
Known hypersensitivity to Dydrogesterone or any of the excipients.
Known or suspected sex hormone dependent malignancies.

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.
Conditions for which monitoring are 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: cholestatic icterus, herpes gestationis, 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.

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 confirmed 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 profile into embryo-foetal and post-natal 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.

The adverse effects of this product most commonly reported in patients who were treated with Dydrogesterone during clinical trials into indications without the use of oestrogen were metrorrhagia, painful/sensitive breasts and migraine/headache.
The following adverse effects, with the frequencies indicated, were observed during clinical trials with Dydrogesterone (n=3,483) for indications without the use of oestrogen, and were reported spontaneously: See table.

Click on icon to see table/diagram/image

Data from in vitro studies show that Dydrogesterone and its main metabolite 20α-dihydrodydrogesterone (DHD) may be broken down by the P450 cytochrome isoenzymes 3A4 and 2C19.
The metabolisation of Dydrogesterone may therefore be increased by concomitant use of substances known to induce these isoenzymes, 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), valerian root, sage, or Gingko biloba.
Ritonavir and nelfinavir are of course well-known powerful inhibitors of cytochrome enzymes but do in fact have an enzyme-inducing action if they are used concomitantly with steroid hormones.
Clinically an increase in the metabolisation of Dydrogesterone may lead to a reduction in effect and changes in the bleeding pattern. In vitro studies show that Dydrogesterone and DHD enzymes that metabolise CYP substances do not inhibit or induce.

Store at temperatures not exceeding 30°C.
Protect from light.

Oestrogens, Progesterones & Related Synthetic Drugs

G03DB01 - dydrogesterone ; Belongs to the class of pregnadien derivative progestogens used in progestogenic hormone preparations.

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