Prescribing Information Duphaston: Tablets

Prescribing Information
DUPHASTON
Tablets
Name of the medicinal product

Duphaston 10mg film-coated tablets
Qualitative and Quantitative Composition

Dydrogesterone film-coated tablets contain 10 mg dydrogesterone per tablet.
Pharmaceutical Form
A round, biconvex, scored, white coloured film-coated tablet, one side bearing the
inscription , the other side bearing the inscription 155 on either side of the break
mark
The score line is only to facilitate breaking for ease of swallowing and not to divide into
equal doses.
Indications
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 insufficiency
Dosage and administration
Dysmenorrhoea : 10 mg twice daily from day 5 to day 25 of the

cycle.
Endometriosis : 10 mg two or three times daily from day 5 to

day 25 of the cycle or continuously.
Dysfunctional bleeding : 10 mg twice daily for five to seven days.

(to arrest bleeding)
Dysfunctional bleeding : 10 mg twice daily from day 11 to day 25 of the

(to prevent bleeding) cycle.
Amenorrhoea : an oestrogen once daily from day 1 to day 25 of
the cycle, together with 10 mg dydrogesterone
twice daily from day 11 to day 25 of the cycle.
Pre-menstrual syndrome : 10 mg twice daily from day 11 to day 25 of the

cycle.
Irregular cycles : 10 mg twice daily from day 11 to day 25 of the

cycle.
Threatened abortion : 40 mg at once, then 10 mg every eight hours

until symptoms remit.
Habitual abortion : 10 mg twice daily until the twentieth week of

pregnancy.
Infertility due to luteal : 10 mg daily from day 14 to 25 of the cycle.

Insufficiency Treatment should be maintained for at least six
consecutive cycles. It is advisable to continue
treatment for the first few months of pregnancy
as described under 'Habitual abortion'.
Duphaston is not recommended for use in children below age 18 due to

insufficient data on safety and efficacy.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Known or suspected progestogen dependent neoplasms.
Undiagnosed vaginal bleeding
Special warnings and precautions for use

Before initiating treatment with dydrogesterone 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.
Breakthrough bleeding may occur in a few patients.
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 Trademark, in
particular:
1. Porphyria
2. Depression
Other conditions
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.
Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.
Pregnancy and lactation

It is estimated that altogether roughly 35 million women have been treated with
dydrogesterone. Although the number of pregnancies is difficult to estimate, as an
approximation it can be assumed that in utero foetuses were exposed to dydrogesterone in
around 9 million pregnancies1. From spontaneous surveillance systems to date, there is
no evidence that dydrogesterone can not be used during pregnancy.
No other relevant epidemiological data on dydrogesterone are available.

However, a recent US case-control study investigating 502 cases with hypospadias and
1286 healthy controls suggested at least a 2-fold increased risk of second/third degree
hypospadias among boys born by mothers who took progestogens (predominantly
progesterone) shortly prior or during early pregnancy (OR 2.2, 95% CI 1.0-5.0). The
causality is unclear as the indication for progesterone in pregnancy may be potential risk
factors for hypospadias. For dydrogesterone, the risk of hypospadias is unknown.
Animal studies have been conducted, however, are insufficient with respect to
pregnancy, embryonal /fetal, or postnatal development due to major difference in
metabolism between rats and humans (for details see section preclinical safety data.
The potential risk for humans is unknown.
Limited animal safety data suggest that dydrogesterone has delaying effects on partuition,
which is consistent with its progestogenic activity.
Dydrogesterone is excreted in the milk of nursing mothers. A risk to the suckling child
cannot be excluded. Dydrogesterone should not be used during breast-feeding.
There is no evidence that dydrogesterone decreases fertility at therapeutic dose.
Effects on ability to drive and use machines

Dydrogesterone has no or negligible influence on the ability to drive and use
machines.
1
This high exposure in pregnancy is due to the fact that dydrogesterone has pregnancy related indications in
large parts of the world.
Undesirable effects
The undesirable effects reported in clinical trials and/or in post marketing experience
following dydrogesterone therapy are:
MedDRA Common Uncommon Rare Very rare

system organ >1/100, <1/10 >1/1,000, >1/10,000, <1/10,000 incl.
class <1/100 <1/1,000 isolated reports
Blood and the Haemolytic

lymphatic anaemia
system disorders
Immune system Hypersensitivity

disorders
Nervous system Migraines/

disorders headache
Hepatobiliary hepatic function

disorders abnormal (with
jaundice,
asthenia or
malaise, and
abdominal pain)
Skin and Dermatitis Angioedema

subcutaneous allergic (e.g.
tissue disorders rash, pruritus,
urticaria)
Reproductive Metrorrhagia Breast pain/

system and tenderness
breast disorders
General Oedema
disorders and
administration
site conditions
Other adverse reactions obtained from the market with unknown frequency in association
with dydrogesterone treatment:
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
Increase in size of progestogen dependent neoplasms (e.g.meningioma) (see section 4.3).
Psychiatric disorders
Depressed mood
Reproductive system and breast disorders

Breast swelling
Overdose
Limited data are available with regard to overdose in humans. Dydrogesterone was well
tolerated after oral dosing (maximum daily dose taken to date in humans 360 mg). No
reports of ill-effects from overdose have been recorded. If a large overdose is
discovered within two or three hours and treatment seems desirable, gastric lavage is
recommended. There are no specific antidotes and treatment should be symptomatic.
Aforementioned information is also applicable for overdosing in children.
Pharmacological properties
Pharmacodynamic properties
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 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.
Pharmacokinetic properties
After oral administration of labeled 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 20-
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 4,6diene-3-one configuration of the parent compound and the absence
of 17-hydroxylation. This explains the lack of estrogenic and androgenic effects 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 Tmax values of dydrogesterone 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.
Preclinical safety data

Receptor binding studies and functional activity studies revealed antiandrogenic potency
of progesterone, dydrogesterone and its metabolite dihydrodydrogesterone (DHD). The
antiandrogenic potency of dydrogesterone and its metabolite DHD is probably noticeably
weaker than that of progesterone. With regard to antiandrogenic effects mediated by
inhibition of 5-reductase type II, an important enzyme for differentiation of the male
external genitalia, progesterone is as potent as the synthetic enzyme inhibitor finasteride,
whereas dydrogesterone and DHD are inactive.
The overall potential to act as antiandrogenic endocrine disruptors may be rated as
highest for Progesterone, lower for Dydrogesterone and lowest for DHD.
Embryofoetal developmental studies were conducted in rats and rabbits using high
dosages of dydrogesterone. No structural adverse effects were recorded in the foetal
offspring. In a subsequent peripostnatal developmental study pregnant rats were treated
with similar dosages of dydrogesterone during the period of gestation, and pups were
raised. There were occasions of hypospadias in the male offspring but only at the highest
dose. The next lower dose of dydrogesterone showed a sufficient safety margin in rat
plasma exposure (>80 fold) compared to the estimated exposure at the maximum human
daily dose of 60 mg. However, due to major species differences in metabolism between
rats and humans, no adequate margin of exposure could be determined for the main
human metabolite dihydrodydrogesterone.
Limited animal safety data suggest that dydrogesterone has delaying effects on
parturition, which is consistent with its progestogenic activity.
Dydrogesterone has been used in several animal models and has been proven to be an
entity with low toxicity, not having mutagenic or carcinogenic properties.
Pharmaceutical particulars
List of excipients
Lactose monohydrate, methylhydroxypropylcellulose, maize starch, colloidal
anhydrous silica, magnesium stearate, Opadry Y-1-7000 white
Incompatibilities
None known
Shelf-life
5 years.
Special precautions for storage

Do not store above 30C. Keep in a dry place.
Keep the blister in the outer carton, in order to protect from moisture.
Nature and contents of container

- Blister strips of aluminium foil and PVC film, coated with PVDC
of 20 tablets
Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local
requirements.
Manufacturer: Solvay Pharmaceuticals
Importer: Perrigo Israel Agencies Ltd.
22.2.2010
The format of this leaflet was determined by the Ministry of Health and its
content was checked and approved by it in February 2010.

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Prescribing Information

Name of the medicinal product

Qualitative and Quantitative Composition

Dosage and administration

Dysmenorrhoea : 10 mg twice daily from day 5 to day 25 of the

Endometriosis : 10 mg two or three times daily from day 5 to

Dysfunctional bleeding : 10 mg twice daily for five to seven days.

Dysfunctional bleeding : 10 mg twice daily from day 11 to day 25 of the

Pre-menstrual syndrome : 10 mg twice daily from day 11 to day 25 of the

Irregular cycles : 10 mg twice daily from day 11 to day 25 of the

Threatened abortion : 40 mg at once, then 10 mg every eight hours

Habitual abortion : 10 mg twice daily until the twentieth week of

Infertility due to luteal : 10 mg daily from day 14 to 25 of the cycle.

Duphaston is not recommended for use in children below age 18 due to

Special warnings and precautions for use

Conditions which need supervision

Interaction with other medicinal products and other forms of interaction

Pregnancy and lactation

No other relevant epidemiological data on dydrogesterone are available.

Effects on ability to drive and use machines

MedDRA Common Uncommon Rare Very rare

Blood and the Haemolytic

Immune system Hypersensitivity

Nervous system Migraines/

Hepatobiliary hepatic function

Skin and Dermatitis Angioedema

Reproductive Metrorrhagia Breast pain/

Reproductive system and breast disorders

After oral administration of dydrogesterone, plasma concentrations of DHD are

Dydrogesterone is rapidly absorbed. The Tmax values of dydrogesterone and DHD

Dydrogesterone is not excreted in urine as pregnanediol, like progesterone. Analysis

Preclinical safety data

Special precautions for storage

Nature and contents of container

Special precautions for disposal

Importer: Perrigo Israel Agencies Ltd.

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