Duphaston (Dydrogesterone)

DUPHASTON (Dydrogesterone) 10mg Film Coated Tablets

Duphaston (Dydrogesterone)

DUPHASTON (Dydrogesterone) 10mg Film Coated Tablets

COMPOSITION

Duphaston 10mg tablets: Each film coated tablet contains 

Dydrogesterone U.S.P. ……… 10mg.

Excipient(s) with known e ect: Each tablet contains 111.1 mg 

Lactose monohydrate

DESCRIPTION

Dydrogesterone is an orally-active progestogen which produces a 

complete secretory endometrium in an oestrogen-primed uterus 

thereby providing protection for oestrogen induced increased risk 

for endometrium hyperplasia and/or carcinogenesis. 

Dydrogesterone has no oestrogenic, no androgenic, no 

thermogenic, no anabolic and no corticoid activity.

Excipients: Lactose monohydrate, Hypromellose, maize starch, 

colloidal anhydrous silica, magnesium stearate, Opadry Y-1-7000 

hite (hypromellose, macrogol 400, titanium dioxide (E171)).

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics

Pharmacotherapeutic group: Genito Urinary system and sex 

hormones

Dydrogesterone is an orally-active progestogen which produces a 

complete secretory endometrium in an oestrogen-primed uterus 

thereby providing protection for estrogen induced increased risk for 

endometrium hyperplasia and/or carcinogenesis. It is indicated in all 

cases of endogenous progesterone deficiency. Dydrogesterone has 

no estrogenic, no androgenic, no thermogenic, no anabolic and no 

corticoid activity.

Pharmacokinetics

After oral administration of labelled dydrogesterone on average 63% 

of the dose is excreted into the urine. Within 72 hours excretion is 

complete. Dydrogesterone is completely metabolized. The main 

metabolite of dydrogesterone is 20a-dihydrodydrogesterone 

(DHD) and is present in the urine predominantly as the glucuronic 

acid conjugate. A common feature of all metabolites characterized is 

the retention of the 4,6-diene-3-one configuration of the parent 

compound and the absence of 17a-hydroxylation. This explains the 

lack of estrogenic and androgenic e ects of dydrogesterone. After 

oral administration of dydrogesterone, plasma concentrations 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. Dydrogesterone is rapidly absorbed. The 

T values of max dydrodesterone and DHD vary between 0.5 and 2.5 

hours. Mean terminal half lives of dydrogesterone and DHD vary 

between 5 to 7 and 14 to 17 hours respectively. Dydrogesterone is 

not excreted in urine as pregnanediol, like progesterone. Analysis of 

endogenous progesterone production based on pregnanediol 

excretion therefore remains possible.

INDICATIONS

Hormone replacement therapy

To counteract the e ects 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.

Progesterone deficiencies

Treatment of progesterone deficiencies such as:

• 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 and habitual abortion, associated with 

proven progesterone deficiency

• Treatment of infertility due to luteal insu ciency

DUPHASTON (Dydrogesterone) 10mg Film Coated Tablets

DOSAGE AND ADMINISTRATION

Dosages, treatment schedule and duration of treatment may be 

adapted to the severity of the dysfunction and the clinical response.

Dysmenorrhoea: 10 or 20mg mg dydrogesterone per day from day 5 to day 25 of the menstrual cycle.

Endometriosis: 10 to 30 mg dydrogesterone per day from day 5 to day 25 of the cycle or continuously.

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 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.

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 30mg per day until symptoms 

remit.

Habitual abortion: 10 mg dydrogesterone twice daily until the twelfth week of pregnancy.

Infertility due to luteal insu ciency: 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 o . 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 e cacy of dydrogesterone in adolescents aged 12-18 
years has not been established. Currently available data are 
described in section 4.8 and 5.1, but no recommendation on a 
posology can be made.
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.
WARNINGS AND SPECIAL 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 a ect 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 favorable 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. Combined estrogen-progestogen therapy: The 
randomized placebo-controlled trial, Women’s Health Initiative 
study (WHI), and 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 years. 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 a ect 
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 o ered 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 thromboembol-
ic 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 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.
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 
age-dependent, the overall risk of stroke in women who use 
HRT will increase with age.
Excipients:
This medicinal product contains Lactose monohydrate.
Patients with rare hereditary problems of galactose intolerance, the 
Lapp lactase deficiency or glucosegalactose malabsorption should 
not take this medicine.
INTERACTIONS
Interaction with other medicinal products and other forms of 
interaction. 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), valerian root, 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 e ect. In vitro studies have shown that dydrogesterone 
and DHD do not inhibit or induce CYP drug metabolizing enzymes 
at clinically relevant concentrations.
PREGNANCY
It is estimated that more than 10 million pregnancies have been 
exposed to dydrogesterone. So far there were no indications of a 
harmful e ect 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.
E ects in non-clinical embryo-fetal and post-natal development 
studies were in line with the pharmacological profile. Untoward 
e ects 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.
Breastfeeding
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.
E ects on ability to drive and use machines
Dydrogesterone has 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.
UNDESIRABLE EFFECTS
Like all medicines, Duphaston may have side e ects. If you notice 
any side e ects not mentioned in this leaflet, please inform your 
doctor or pharmacist.
The frequencies of study related adverse events are ranked 
according to the following: common (frequency 1.10%), uncommon 
(frequency <1%), rare (frequency <0.1%), very rare (frequency 
<0.01%), including isolated reports.
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 e ects have been observed with the 
frequencies indicated below during clinical trials using 
dydrogesterone (n=3483) in indications without estrogen treatment 
and from spontaneous reporting: