Sverige - svenska - Läkemedelsverket (Medical Products Agency)
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Endofemine 2 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2 mg dienogest
Excipient with known effect: each tablet contains 60.9 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
White, round, tablets with a diameter of 5 mm.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of endometriosis.
4.2 Posology and method of administration
The dosage of <INVENTED NAME> is one tablet daily without any break, taken preferably at
the same time each day with some liquid as needed. The tablet can be taken with or without
Tablets must be taken continuously without regard to vaginal bleeding. When a pack is finished
the next one should be started without interruption.
There is no experience with <INVENTED NAME> treatment >15 months in patients with
Treatment can be started on any day of the menstrual cycle.
Any hormonal contraception needs to be stopped prior to initiation of <INVENTED NAME>.
If contraception is required, non-hormonal methods of contraception should be used (e.g.
Management of missed tablets:
The efficacy of <INVENTED NAME> may be reduced in the event of missed tablets, vomiting
and/or diarrhea (if occuring within 3-4 hours after tablet taking). In the event of one or more
missed tablets, the woman should take one tablet only, as soon as she remembers, and should
then continue the next day at her usual time. A tablet not absorbed due to vomiting or diarrhea
should likewise be replaced by one tablet.
Additional information on special populations
<INVENTED NAME> is not indicated in children prior to menarche.
The safety and efficacy of dienogest was investigated in an uncontrolled clinical trial over 12
endometriosis (see sections 4.4 and 5.1).
There is no relevant indication for use of <INVENTED NAME> in the Geriatric population.
Patients with hepatic impairment:
<INVENTED NAME> is contraindicated in patients with present or past severe hepatic disease
(see section 4.3).
Patients with renal impairment:
Method of administration:
For oral use.
<INVENTED NAME> should not be used in the presence of any of the conditions listed below,
which are partially derived from information on other progesteron-only preparations. Should
any of the conditions appear during the use of <INVENTED NAME>, treatment must be
active venous thromboembolic disorder
arterial and cardiovascular disease, past or present (e.g. myocardial infarction, cerebrovascular
accident, ischemic heart disease)
diabetes mellitus with vascular involvement
presence or history of severe hepatic disease as long as liver function values have not returned
presence or history of liver tumours (benign or malignant)
known or suspected sex hormone-dependent malignancies
undiagnosed vaginal bleeding
hypersensitivity to the active substance or to any of the excipients listed in Section 6.1
4.4 Special warnings and precautions for use
As <INVENTED NAME> is a progestogen-only preparation it can be assumed that the special
warnings and precautions for use of progestogen-only preparations are also valid for the use of
respective findings in the clinical studies with dienogest.
If any of the conditions/risk factors mentioned below is present or deteriorates, an individual
risk-benefit analysis should be done before treatment with <INVENTED NAME> can be
started or continued.
Serious uterine bleeding
Uterine bleeding, for example in women with adenomyosis uteri or uterine leiomyomata, may
be aggravated with the use of <INVENTED NAME>. If bleeding is heavy and continuous over
time, this may lead to anemia (severe in some cases). In the event of anemia, discontinuation of
<INVENTED NAME> should be considered.
Changes in bleeding pattern
The majority of patients treated with dienogest experience changes in their menstrual bleeding
pattern (see section 4.8).
From epidemiological studies there is little evidence for an association between progestogen-
only preparations and an increased risk of myocardial infarction or cerebral thromboembolism.
Rather, the risk of cardiovascular and cerebral events is related to increasing age, hypertension,
and smoking. In women with hypertension the risk of stroke may be slightly enhanced by
Although not statistically significant, some studies indicate that there may be a slightly
increased risk of venous thromboembolism (deep venous thrombosis, pulmonary embolism)
associated with the use of progestogen-only preparations. Generally recognized risk factors for
venous thromboembolism (VTE) include a positive personal or family history (VTE in a
sibling or a parent at a relatively early age), age, obesity, prolonged immobilization, major
surgery or major trauma. In case of long-term immobilization it is advisable to discontinue the
use of <INVENTED NAME> (in the case of elective surgery at least four weeks in advance)
and not to resume treatment until two weeks after complete remobilization.
The increased risk of thromboembolism in the puerperium must be considered.
Treatment should be stopped at once if there are symptoms of an arterial or venous thrombotic
event or suspicion thereof.
A meta-analysis from 54 epidemiological studies reported that there is a slightly increased
relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using
oral contraceptives (OCs), mainly using estrogen-progestogen preparations. The excess risk
gradually disappears during the course of the 10 years after cessation of combined OC (COC)
use. Because breast cancer is rare in women under 40 years of age, the excess number of breast
cancer diagnoses in current and recent COC users is small in relation to the overall risk of
breast cancer. The risk of having breast cancer diagnosed in users of progestogen-only
preparations is possibly of similar magnitude to that associated with COC. However, for
progestogen-only preparations, the evidence is based on much smaller populations of users and
so is less conclusive than that for COCs. These studies do not provide evidence for causation.
The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in
OC users, the biological effects of OCs or a combination of both. The breast cancers diagnosed
in users of OCs tend to be less advanced clinically than the cancers diagnosed in those who
have never used OCs.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been
reported in users of hormonal substances such as the one contained in <INVENTED NAME>.
In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A
hepatic tumour should be considered in the differential diagnosis when severe upper abdominal
pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking
Changes in bone mineral density (BMD).
The use of dienogest in adolescents (12 to <18 years) over a treatment period of 12 months was
associated with a decrease in bone mineral density (BMD) in the lumbar spine (L2-L4). The
mean relative change in BMD from baseline to the end of treatment (EOT) was - 1.2% with a
range between -6% and 5% (IC 95%: -1.70% and -0.78%, n=103.
Repeated measurement at 6 months after the EOT in a subgroup with decreased BMD values
showed a trend towards recovery. (Mean relative change from baseline: –2.3% at EOT and –
0.6% at 6 months after EOT with a range between -9% and 6% (IC 95%: -1.20% and 0.06%
Loss of BMD is of particular concern during adolescence and early adulthood, a critical period
of bone accretion. It is unknown if BMD decrease in this population will reduce peak bone
mass and increase the risk for fracture in later life (see sections 4.2 and 5.1).
In patients who are at an increased risk of osteoporosis a careful risk-benefit assessment should
be performed before starting <INVENTED NAME> because endogenous estrogen levels are
moderately decreased during treatment with <INVENTED NAME> (see section 5.1).
Adequate intake of calcium and Vitamin D, whether from the diet or from supplements, is
important for bone health in women of all ages.
Patients who have a history of depression should be carefully observed and the drug should be
discontinued if the depression recurs to a serious degree.
<INVENTED NAME>, it is advisable to withdraw <INVENTED NAME> and treat the
Recurrence of cholestatic jaundice and/or pruritus which occurred first during pregnancy or
previous use of sex steroids necessitates the discontinuation of <INVENTED NAME>.
Dienogest may have a slight effect on peripheral insulin resistance and glucose tolerance.
Diabetic women, especially those with a history of gestational diabetes mellitus, should be
carefully observed while taking <INVENTED NAME>.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum.
Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation
whilst taking <INVENTED NAME>.
Pregnancies that occur among users of progestogen-only preparations used for contraception
Therefore, in women with a history of extrauterine pregnancy or an impairment of tube
function, the use of <INVENTED NAME> should be decided on only after carefully weighing
the benefits against the risks.
Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during the
use of <INVENTED NAME>. Most of these follicles are asymptomatic, although some may be
accompanied by pelvic pain.
Each <INVENTED NAME> tablet contains 60.9 mg of lactose monohydrate. Patients with rare
hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose
malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Note: The prescribing information of concomitant medication should be consulted to identify
Effects of other medication on <INVENTED NAME>
Progestogens including dienogest are metabolized mainly by the cytochrome P450 3A4 system
(CYP3A4) located both in the intestinal mucosa and in the liver. Therefore, inducers or
inhibitors of CYP3A4 may affect the progestogen drug metabolism.
An increased clearance of sex hormones due to enzyme induction may reduce the therapeutic
effect of <INVENTED NAME> and may result in undesirable effects e.g. changes in the
uterine bleeding profile.
A reduced clearance of sex hormones due to enzyme inhibition may increase the exposure to
dienogest and may result in undesirable effects.
- Substances increasing the clearance of sex hormones (diminished efficacy by enzyme-
oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing St. John’s wort
Enzyme induction can already be observed after a few days of treatment. Maximum enzyme
induction is generally seen within a few weeks. After cessation of drug therapy enzyme
induction may be sustained for about 4 weeks.
The effect of the CYP 3A4 inducer rifampicin was studied in healthy postmenopausal women.
Co-administration of rifampicin with estradiol valerate/dienogest tablets led to significant
decreases in steady state concentrations and systemic exposures of dienogest and estradiol. The
systemic exposure of dienogest and estradiol at steady state, measured by AUC(0-24h), were
decreased by 83% and 44%, respectively.
- Substances with variable effects on the clearance of sex hormones:
When co-administered with sex hormones, many combinations of HIV protease inhibitors and
non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors
can increase or decrease plasma concentrations of the progestin. The net effect of these changes
may be clinically relevant in some cases.
- Substances decreasing the clearance of sex hormones (enzyme inhibitors)
Dienogest is a substrate of cytochrome P450 (CYP) 3A4.
The clinical relevance of potential interactions with enzyme inhibitors remains unknown.
Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations
Coadministration with the strong CYP3A4 enzyme inhibitor ketoconazole resulted in a 2.9-fold
increase of AUC (0- 24h) at steady state for dienogest. Concomitant administration of the
moderate inhibitor erythromycin increased the AUC (0-24h) of dienogest at steady state by 1.6-
Effects of dienogest 2mg on other medication
inhibition studies, a clinically relevant interaction of dienogest with the
cytochrome P450 enzyme mediated metabolism of other medication is unlikely.
Interaction with food.
A standardized high fat meal did not affect the bioavailability of dienogest 2 mg
The use of progestogens may influence the results of certain laboratory tests, including
biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier)
proteins (e.g. corticosteroid binding globulin and lipid/lipoprotein fractions), parameters of
carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally
remain within the normal laboratory range.
4.6 Fertility, pregnancy and lactation
There is limited data from the use of dienogest in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive
toxicity (see section 5.3).
<INVENTED NAME> must not be administered to pregnant women because there is no need
to treat endometriosis during pregnancy.
Treatment with <INVENTED NAME> during lactation is not recommended.
It is unknown wheter dienogest is excreted in human milk. Data in animals have shown
excretion of dienogest in rat milk.
<INVENTED NAME> therapy taking into account the benefit of breast-feeding for the child
and the benefit of therapy for the woman.
Based on the available data, ovulation is inhibited in the majority of patients during treatment
with dienogest. However, <INVENTED NAME> is not a contraceptive.
If contraception is required a non-hormonal method should be used (See section 4.2).
Based on available data, the menstrual cycle returns to normal within 2 months after cessation
of treatment with <INVENTED NAME>.
4.7 Effects on ability to drive and use machines
No effects on the ability to drive and use machines have been observed in users of products
4.8 Undesirable effects
Presentation of undesireable effects is based on MedDRA.
The most appropriate MedDRA term is used to describe a certain reaction and its synonyms
and related conditions
Undesirable effects are more common during the first months after the start of treatment with
<INVENTED NAME>, and subside with continued treatment. There may be changes in
bleeding pattern, such as spotting, irregular bleeding or amenorrhea. The following undesirable
effects have been reported in users of Dienogest 2mg tablets.
The most frequently reported undesirable effects under treatment with Dienogest 2 mg are
headache (9.0%), breast discomfort (5.4%), depressed mood (5.1 %) and acne (5.1 %).
menstrual bleeding pattern. Menstrual bleeding patterns were assessed systematically using
patient diaries and were analyzed using the WHO 90 days reference period method. During the
first 90 days of treatment with Dienogest 2mg the following bleeding patterns were observed
(n=290; 100%): Amenorrhea (1.7%), infrequent bleeding (27.2%), frequent bleeding (13.4%),
irregular bleeding (35.2%), prolonged bleeding (38.3%), normal bleeding, i.e. none of the
previous categories (19.7%). During the fourth reference period the following bleeding patterns
were observed (n=149; 100%): Amenorrhea (28.2%), infrequent bleeding (24.2%), frequent
bleeding (2.7%), irregular bleeding (21.5%), prolonged bleeding (4.0%), normal bleeding, i.e.
none of the previous categories (22.8%). Changes in menstrual bleeding patterns were only
occasionally reported as adverse event by the patients (See adverse event table).
(MedDRA SOCs) reported with Dienogest 2 mg are summarized in the table below. Within
each frequency grouping, undesirable effects are presented in order of decreasing frequency.
Frequencies are defined as common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100).
The frequencies are based on pooled data of four clinical trials, including 332 patients (100%).
Table 1, Adverse reactions table, phase III clinical trials, N= 332
System Organ Class
loss of libido
Nervous system disorders
autonomic nervous system imbalance
disturbance in attention
Ear and labyrinth disorders
System Organ Class
abnormal hair growth
pain in extremity
heaviness in extremities
Renal and urinary disorders
urinary tract infection
Reproductive system and breast
fibrocystic breast disease
administration site conditions
Decrease of bone mineral density
In an uncontrolled clinical trial with 111 adolescent women (12 to <18 years) who were treated
with dienogest, 103 had BMD measurements. Approximately 72% of these study participants
experienced a decrease in BMD of the lumbar spine (L2-L4) after 12 months of use (see section
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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 the national reporting
system listed in Appendix V.
Acute toxicity studies performed with dienogest did not indicate a risk of acute adverse effects
in case of inadvertent intake of a multiple of the daily therapeutic dose. There is no specific
antidote. A daily intake of 20 - 30 mg dienogest (10 to 15 times higher dose than in
<INVENTED NAME>) over 24 weeks of use was very well tolerated.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: progestogens; ATC code: G03DB08
Dienogest is a nortestosterone derivative with no androgenic but rather an antiandrogenic
activity of approximately one third of that of cyproterone acetate. Dienogest binds to the
progesterone. Despite its low affinity to the progesterone receptor, dienogest has a strong
progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid or
Dienogest acts on endometriosis by reducing the endogenous production of oestradiol and
thereby suppresses the trophic effects of estradiol on both the eutopic and ectopic endometrium.
When given continuously, dienogest leads to a hypoestrogenic, hypergestagenic endocrine
environment causing initial decidualization of endometrial tissue followed by atrophy of
Data on efficacy:
Superiority of dienogest over placebo was demonstrated in a 3-months study including 198
patients with endometriosis. Endometriosis-associated pelvic pain was measured on a Visual
Analog Scale (0-100 mm). After 3 months of treatment with Dienogest 2 mg a statistically
significant difference compared to placebo (Δ = 12.3 mm; 95%CI: 6.4 – 18.1; p<0.0001) and a
clinically meaningful reduction of pain compared to baseline (mean reduction = 27.4 mm ±
22.9) were demonstrated.
After 3 months of treatment, reduction of endometriosis-associated pelvic pain by 50% or more
without relevant increase of concomitant pain medication was achieved in 37.3% of patients on
Dienogest 2 mg (placebo: 19.8%); a reduction of endometriosis-associated pelvic pain by 75%
or more without relevant increase of concomitant pain medication was achieved in 18.6% of
patients on Dienogest 2mg (placebo: 7.3%).
The open-label extension to this placebo-controlled study suggested a continued improvement
of endometriosis-associated pelvic pain for a treatment duration of up to 15 months.
The placebo controlled results were supported by the results obtained in a 6 months active-
controlled study versus a GnRH agonist including 252 patients with endometriosis.
Three studies including a total of 252 patients who received a daily dose of 2 mg dienogest
demonstrated a substantial reduction of endometriotic lesions after 6 months of treatment.
In a small study (n=8 per dose group), a daily dose of 1 mg dienogest has been shown to induce
an anovulatory state after 1 month of treatment. Dienogest 2 mg has not been tested for
contraceptive efficacy in larger studies.
Data on safety
Endogenous estrogen levels are moderately suppressed during treatment with Dienogest 2 mg.
Currently, long-term data on bone mineral density (BMD) and risk of fractures in users of
Dienogest 2 mg are not available. BMD was assessed in 21 patients before and after 6 months
of treatment with Dienogest 2 mg and there was no reduction of mean BMD. In 29 patients
treated with leuprorelin acetate (LA), a mean reduction of 4.04% ± 4.84 was noted after the
same period (Δ between groups = 4.29%; 95%CI: 1.93 – 6.66; p<0.0003).
No significant changes of the mean values of standard laboratory parameters (including
haematology, blood chemistry, liver enzymes, lipids and HbA1C) were observed during
treatment with Dienogest 2 mg for up to 15 months (n=168).
Safety in adolescents
The safety of dienogest with respect to BMD was investigated in an uncontrolled clinical trial
over 12 months in 111 adolescent women (12 to <18 years) with clinically suspected or
confirmed endometriosis. The mean relative change in BMD of the lumbar spine (L2-L4) from
baseline in the 103 patients with BMD measurement was -1.2 %. In a subset of the patients
with decreased BMD a follow-up measurement was performed 6 months after end of treatment
and showed an increase in BMD to -0.6%.
5.2 Pharmacokinetic properties
concentrations of 47 ng/ml are reached at about 1.5 hours after single ingestion. Bioavailability
is about 91%. The pharmacokinetics of dienogest are dose-proportional within the dose range
of 1 - 8 mg.
Dienogest is bound to serum albumin and does not bind to sex hormone binding globulin
(SHBG) or corticoid binding globulin (CBG). 10 % of the total serum drug concentration is
present as free steroid, 90 % is non-specifically bound to albumin.
The apparent volume of distribution (V
/F) of dienogest is 40 l.
Dienogest is completely metabolized by the known pathways of steroid metabolism, with the
formation of endocrinologically mostly inactive metabolites. Based on in vitro and in vivo
metabolites are excreted very quickly so that in plasma unchanged dienogest is the dominating
The metabolic clearance rate from serum Cl/F is 64 ml/min.
Dienogest serum levels decrease in two phases. The terminal disposition phase is characterized
by a half-life of approximately 9-10 hours. Dienogest is excreted in form of metabolites which
are excreted at a urinary to faecal ratio of about 3:1 after oral administration of 0.1 mg/kg. The
approximately 86% of the dose administered is eliminated within 6 days, the bulk of this
amount excreted within the first 24 h, mostly with the urine.
Pharmacokinetics of dienogest are not influenced by SHBG levels. Following daily ingestion
drug serum levels increase about 1.24 fold reaching steady-state conditions after 4 days of
treatment. The pharmacokinetics of dienogest after repeated administration of <INVENTED
NAME> can be predicted from single dose pharmacokinetics.
Pharmacokinetics in Special Population
<INVENTED NAME> has not been studied specifically in renally impaired subjects.
<INVENTED NAME> has not been studied in subjects with hepatic impairment.
5.3 Preclinical safety data
Preclinical data reveal no special risks for humans based on conventional studies of repeated
dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it
should be borne in mind that sex steroids can promote the growth of certain hormone-
dependent tissues and tumours.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
6.3 Shelf life
6.4 Special precautions for storage
Store in the
to protect from light
6.5 Nature and contents of container
The tablets are contained in blister packs of aluminium push-through foil and PVC-PVDC
1 x 28 tablets (calendar pack)
3 x 28 tablets (calendar pack)
6 x 28 tablets (calendar pack)
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local
7. MARKETING AUTHORISATION HOLDER
<to be completed nationally>
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
<to be completed nationally>
10. DATE OF REVISION OF THE TEXT