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
Pharmacotherapeutic group: Genito Urinary system and sex hormones
ATC code: G03DB01
Dydrogesterone is an orally-active progestogen, which produces a complete secretory endometrium in an estrogen-primed uterus, thereby providing protection for estrogen-induced increased risk of endometrial hyperplasia and/or carcinogenesis. It is indicated in all cases of endogenous progesterone deficiency. Duphaston is non-androgenic, non-estrogenic, non-thermogenic, non-corticoid and non-anabolic.
When used in conjunction with an estrogen, the pharmacodynamic properties relating to the particular estrogen used should also be considered, for example:
Following oral administration, dydrogesterone is rapidly absorbed with a Tmax between 0.5 and 2.5 hours. The absolute bioavailability of dydrogesterone (oral 20 mg dose versus 7.8 mg intravenous infusion) is 28%.
The following table provide pharmacokinetic parameters of dydrogesterone (D) and 20ฮฑ-dihydrodydrogesterone (DHD) after single dose administration of 10 mg dydrogesterone:
| D | DHD | |
|---|---|---|
| Cmax (ng/mL) | 2.1 | 53.0 |
| AUCinf (ngยทh/mL) | 7.7 | 322.0 |
After intravenous administration of dydrogesterone the steady-state volume of distribution is approximately 1400 L. Dydrogesterone and DHD are more than 90% bound to plasma proteins.
Following oral administration, dydrogesterone is rapidly metabolized to DHD. The levels of the main active metabolite DHD peak about 1.5 hours postdose. The plasma levels of DHD are substantially higher as compared to the parent drug. The AUC and Cmax ratios of DHD to dydrogesterone are in the order of 40 and 25, respectively. Mean terminal half lives of dydrogesterone and DHD vary between 5 to 7 and 14 to 17 hours, respectively. A common feature of all metabolites characterised is the retention of the 4,6 diene-3-one configuration of the parent compound and the absence of 17ฮฑ-hydroxylation. This explains the lack of estrogenic and androgenic effects of dydrogesterone.
After oral administration of labelled dydrogesterone, on average 63% of the dose is excreted into the urine. Total plasma clearance is 6.4 L/min. Within 72 hours excretion is complete. DHD is present in the urine predominantly as the glucuronic acid conjugate.
The single and multiple dose pharmacokinetics are linear in the oral dose range 2.5 to 10 mg. Comparison of the single and multiple dose kinetics shows that the pharmacokinetics of dydrogesterone and DHD are not changed as a result of repeated dosing. Steady state was reached after 3 days of treatment.
Non-clinical data obtained from conventional studies on single and repeated dose toxicity, genotoxicity and carcinogenic potential reveal no special hazard for humans.
Reproduction toxicity studies in rats have shown an increased incidence of prominent nipples (between day 11 and day 19 of age) and of hypospadias in the male offspring at high dosages not comparable to human exposure. The actual risk of hypospadias in humans cannot be determined in animal studies due to major species differences in metabolism between rats and humans (see also section 4.6)
Limited animal safety data suggest that dydrogesterone has prolongating effects on parturition, which is consistent with its progestogenic activity.
Environmental Risk assessment: Environmental assessment studies have shown that dydrogesterone, may pose a risk to the aquatic environment.
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