Dienogest León Farma 2 mg Tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

16-12-2018

Produktens egenskaper Produktens egenskaper (SPC)

07-06-2019

Aktiva substanser:
dienogest
Tillgänglig från:
Laboratorios Leon Farma S.A.
ATC-kod:
G03DB08
INN (International namn):
dienogest
Dos:
2 mg
Läkemedelsform:
Tablett
Sammansättning:
laktosmonohydrat Hjälpämne; dienogest 2 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 1 x 28 tabletter (kalenderförpackning); Blister, 3 x 28 tabletter (kalenderförpackning); Blister, 6 x 28 tabletter (kalenderförpackning)
Bemyndigande status:
Godkänd
Godkännandenummer:
57387
Tillstånd datum:
2019-06-07

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

16-12-2018

Produktens egenskaper Produktens egenskaper - engelska

16-12-2018

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

26-06-2019

Läs hela dokumentet

PACKAGE LEAFLET: INFORMATION FOR THE USER

Dienogest León Farma 2 mg tablets

Dienogest

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

- Keep this leaflet. You may need to read it again.

- If you have any further questions, ask your doctor or pharmacist.

- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even

if their symptoms are the same as yours.

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What <INVENTED NAME> is and what it is used for

2. What you need to know before you take <INVENTED NAME>

3. How to take <INVENTED NAME>

4. Possible side effects

5. How to store <INVENTED NAME>

6. Contents of the pack and other information

1.

What <INVENTED NAME> is and what it is used for

<INVENTED NAME> is a preparation for the treatment of endometriosis (painful symptoms

due to displaced tissue of the lining of the womb). <INVENTED NAME> contains a hormone,

the progestogen dienogest.

2.

What you need to know before you take <INVENTED NAME>

DO NOT take <INVENTED NAME> if you

are suffering from a

blood clot

(thromboembolic disorder) in your veins. This may occur, for

example, in the blood vessels of the legs (deep vein thrombosis) or the lungs (pulmonary

embolism). See also

“<INVENTED NAME> and venous blood clots”

below

have or have ever had a

severe arterial disease

, including cardiovascular disease, such as a

heart attack

stroke

heart disease

which causes a reduced blood supply (angina pectoris).

See also

"<INVENTED NAME> and arterial blood clots"

below

have

diabetes

with blood vessel damage

have or have ever had

severe liver disease

(and your liver function values have not returned to

normal). Symptoms of liver disease may be yellowing of the skin and/or itching of the whole

body

have or have ever had a

benign or malignant liver tumour

suffer or have ever suffered, or if it is suspected that you suffer from a

malignant

sex-

hormone dependent tumour such as cancer of the breast or the genital organs

have any unexplained

vaginal bleeding

are

allergic (hypersentitive)

to dienogest or any of the other ingredients of <INVENTED

NAME> (listed in section 6 and end of Section 2)

If any of these conditions appear for the first time while using <INVENTED NAME>, stop

taking it at once and consult your doctor.

Warnings and precautions

You must not use hormonal contraceptives of any form (tablet, patch, intrauterine system) while

taking <INVENTED NAME>.

<INVENTED NAME> is NOT a contraceptive. If you want to prevent pregnancy, you should

use condoms or other non-hormonal contraceptive precautions.

In some situations you need to take special care while using <INVENTED NAME>, and your

doctor may need to examine you regularly. Tell your doctor if any of the following conditions

applies to you:

If you:

have ever had a

blood clot

(venous thromboembolism) or anyone in your immediate

family has had a blood clot at a relatively early age

have a close relative who has had

breast cancer

have ever suffered from

depression

have

high blood pressure

or develop high blood pressure while taking <INVENTED

NAME>

develop a

liver disease

while taking <INVENTED NAME>. Symptoms may include

yellowing of the skin or eyes or itching all over your body. Inform your doctor also if

such symptoms occurred during a previous pregnancy

have diabetes or had

diabetes

temporarily during previous pregnancy

have ever had

chloasma

(golden-brown patches on the skin, particularly of the face); if

so, avoid too much exposure to the sun or ultraviolet radiation

suffer from

pain in your lower abdomen

while taking <INVENTED NAME>.

While taking <INVENTED NAME> your chance of becoming pregnant is reduced because

<INVENTED NAME> may affect ovulation.

If you become pregnant while taking <INVENTED NAME> you are at

a slightly increased

risk

of having an extrauterine pregnancy (the embryo develops outside the womb). Tell your

doctor before you start taking <INVENTED NAME>, if you had an extrauterine pregnancy in

the past or have an impaired function of the Fallopian tubes.

<INVENTED NAME> and serious uterine bleeding

Uterine bleeding, for example in women with a condition where the mucous membrane of your

uterus (endometrium) grows into the muscle layer of your uterus, called adenomyosis uteri or

benign tumours of the womb

sometimes called uterine fibroids (uterine leiomyomata), may

become worse with the use of <INVENTED NAME>. If bleeding is heavy and continuous over

time, this may lead to low red blood cell levels (anemia), which may be severe in some cases. In

event

anemia,

should

discuss

with

your

doctor

should

stop

taking

<INVENTED NAME>.

<INVENTED NAME> and changes in bleeding pattern

Most

women

treated

with

<INVENTED

NAME>

experience

changes

their

menstrual

bleeding pattern (see section 4, possible side effects).

<INVENTED NAME> and venous blood clots

Some studies indicate that there may be a slight, but not statistically significant, increased risk

of a

blood clot in the legs (venous thromboembolism)

associated with the use of preparations

with progestagens like <INVENTED NAME>. Very rarely, blood clots may cause serious

permanent disabilities or may even be fatal.

The risk of a

venous blood clot

increases:

with increasing age

if you are overweight

if you or one of your close relatives had a blood clot in the leg (thrombosis), lung (pulmonary

embolism), or other organ at a young age

if you must have surgery, if you have had a serious accident or if you are immobilized for a

long time. It is important to tell your doctor in advance that you are using <INVENTED

NAME> as the treatment may have to be stopped. Your doctor will tell you when to start

<INVENTED NAME> again. This is usually about two weeks after you are back on your feet

<INVENTED NAME> and arterial blood clots

There

little

evidence

association

between

preparations

with

progestagens

like

<INVENTED NAME> and an increased risk of a blood clot in, for example, the bloodvessels of

the heart (heart attack) or the brain (stroke). In women with hypertension the risk of stroke may

be slightly enhanced by these preparations.

The risk of an

arterial blood clot

increases:

if you smoke. You are strongly advised to stop smoking when you use <INVENTED

NAME>, especially if you are older than 35 years.

if you are overweight

if one of your close relatives had a heart attack or stroke at a young age

if you have high blood pressure

Talk to your doctor before taking <INVENTED NAME>

Stop taking <INVENTED NAME> and contact your doctor immediately if you notice

possible signs of a blood clot, such as:

severe pain and/or swelling in one of your legs

sudden severe pain in the chest which may reach the left arm

sudden breathlessness

sudden cough without an obvious cause

any unusual, severe or long-lasting headache or worsening of migraine

partial or complete blindness or double vision

difficulty in speaking or inability to speak

giddiness or fainting

weakness, strange feeling, or numbness in any part of the body

<INVENTED NAME> and cancer

It is not clear from the data currently available whether or not <INVENTED NAME> increases

the risk of breast cancer. Breast cancer has been observed slightly more often in women taking

hormones compared to those not taking hormones, but it is not known whether this is caused by

the treatment. For example, it may be that more tumours are detected and detected earlier in

women taking hormones because they are examined by their doctor more often. The occurrence

of breast tumours becomes gradually less after stopping the hormone treatment.

It is important

to regularly check your breasts

and you should contact your doctor if you feel any lump.

In rare cases, benign liver tumours, and in even fewer cases malignant liver tumours have been

reported in women taking hormones. Contact your doctor if you have unusually severe stomach

pain.

<INVENTED NAME> and osteoporosis

Changes in bone mineral density (BMD)

The use of <INVENTED NAME> may affect the strength of the bone of adolescents (12 to

under 18 years). If you are under 18 your doctor will, therefore, carefully weigh the benefits and

risks of using <INVENTED NAME> for you as an individual patient, taking into account

possible risk factors for bone loss (osteoporosis).

If you use <INVENTED NAME>, it will help your bones if you have an adequate intake of

calcium and vitamin D either via your food or via supplements.

If you have an increased risk of getting osteoporosis (weakening of bones due to loss of bone

minerals),

your

doctor

will

carefully

weigh

risks

benefits

treatment

with

<INVENTED NAME> because <INVENTED NAME> has a moderate suppressing effect on

the production of oestrogen (another type of female hormone) by your body.

Other medicines and <INVENTED NAME>

Always tell your doctor which medicines or herbal products you are already using. Also tell any

other doctor or dentist who prescribes another medicine (or the pharmacist) that you are taking

<INVENTED NAME>.

Some medicines can have an influence on the blood levels of <INVENTED NAME> and can

make it less effective, or can cause undesirable effects.

These include:

medicines used for the treatment of

epilepsy

(e.g. phenytoin, barbiturates, primidone, carbamazepine, oxcarbazepine,

topiramate, felbamate)

tuberculosis (

e.g. rifampicin

)

HIV and Hepatitis C Virus infections

(so called protease inhibitors and non-

nucleoside

reverse

transcriptase

inhibitors

such

ritonavir,

nevirapine,

efavirenz)

fungal infections

(griseofulvin, ketoconazole)

the herbal remedy

St. John’s

wort

Ask your doctor or pharmacist for advice before taking any medicine.

<INVENTED NAME> with food and drink

During Visanne treatment, you should avoid drinking grapefruit juice, because this may

increase the levels of Visanne in your blood. This may increase the risk of getting side effects.

Laboratory tests

If you need a blood test, tell your doctor or the laboratory staff that you are taking <INVENTED

NAME>, because <INVENTED NAME> can affect the results of some tests.

Pregnancy and breast-feeding

Do not take <INVENTED NAME> if you are pregnant or breast-feeding.

Driving and using machines

No effects on the ability to drive and use machines have been observed in users of <INVENTED

NAME>.

<INVENTED NAME> contains lactose.

If you have been told by your doctor that you have an intolerance to some sugars, contact your

doctor before taking this medicinal product.

Children and adolescents

Visanne is not for use in girls before menarche (first menstrual bleeding).

The use of Visanne may affect the strength of the bone of adolescents (12 to under 18 years). If

you are under 18 your doctor will, therefore, carefully weigh the benefits and risks of using

Visanne for you as an individual patient, taking into account possible risk factors for bone loss

(osteoporosis).

3.

HOW TO TAKE <INVENTED NAME>

Always take <INVENTED NAME> exactly as your doctor has told you. You should check with

your doctor or pharmacist if you are not sure. For adults, the usual dose is 1 tablet per day.

The following statements apply to <INVENTED NAME> unless otherwise prescribed by your

doctor. Please follow these instructions, otherwise you will not fully benefit from <INVENTED

NAME>.

You can start treatment with <INVENTED NAME> on any day of your natural cycle.

Adults: take one tablet every day, preferably at the same time with some liquid as needed. When

a pack is finished the next one should be started without interruption. Continue to take the

tablets also on days of menstrual bleeding.

There is no experience with <INVENTED NAME> treatment >15 months in patients with

endometriosis.

If you take more <INVENTED NAME> than you should

There have been no reports of serious harmful effects from taking too many <INVENTED

NAME> tablets at one time. However, if you are concerned, contact your doctor.

If you forget to take <INVENTED NAME> or suffer from vomiting or diarrhoea

<INVENTED NAME> will be less effective if you miss a tablet. If you miss one or more

tablets, take one tablet only as soon as you remember, and then continue next day taking the

tablet at your usual time.

If you vomit within 3-4 hours of taking <INVENTED NAME> or you have severe diarrhoea,

there is a risk that the active substance in the tablet will not be taken up by your body. The

situation is almost the same as forgetting a tablet. After vomiting or diarrhoea within 3-4 hours

of taking <INVENTED NAME>, you should take another tablet as soon as possible.

Do not take a double dose to make up for a forgotten tablet.

If you stop taking <INVENTED NAME>

If you stop taking <INVENTED NAME>, your original endometriosis symptoms may return.

4.

POSSIBLE SIDE EFFECTS

Like all medicines, <INVENTED NAME> can cause side effects, although not everybody gets

them.

These

effects

more

common

during

first

months

after

start

intake

<INVENTED NAME> and usually disappear with continued use. You may also experience

changes in your bleeding pattern, such as spotting, irregular bleeding or your periods may stop

completely.

Common (affecting between 1 and 10 in every 100 users)

- weight gain

- depressed mood, problems sleeping, nervousness, loss of interest in sex, or changed mood

- headache or migraine

- nausea, abdominal pain, wind, swollen tummy or vomiting

- acne or hair loss

- back pain

- breast discomfort, ovarian cyst or hot flushes

- uterine/vaginal bleeding including spotting

- weakness or irritability

Uncommon (affecting between 1 and 10 in every 1,000 users)

- anemia

- weight loss or increase in appetite

- anxiety, depression or mood swings

- imbalance in the autonomic nervous system (controls unconscious bodily functions, e.g.

perspiration) or disturbed attention

- dry eye

- tinnitus

- unspecific circulatory problems or uncommon palpitations

- low blood pressure

- shortness of breath

- diarrhoea, constipation, abdominal discomfort, inflammation of the stomach and intestines

(gastrointestinal inflammation), inflammation of the gums (gingivitis)

- dry skin, excessive sweating, severe itching of the whole body, male pattern hair growth

(hirsutism), brittle nails, dandruff, dermatitis, abnormal hair growth, hypersensitive response

to light or problems with skin pigmentation

- pains in your bones, muscle spasms, pains and/or a sensation of heaviness in your arms and

hands or legs and feet

- urinary tract infection

vaginal

thrush,

dryness

genital

area,

vaginal

discharge,

pelvic

pain,

atrophic

inflammation of the genitals with discharge (atrophic vulvovaginitis), or a lump or lumps in

the breast

- swelling due to fluid retention

Additional side effects in adolescents (12 to under 18 years): loss of bone density.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via the national

reporting system listed in Appendix V. By reporting side effects you can help provide more

information on the safety of this medicine.

5.

HOW TO STORE <INVENTED NAME>

Store in the outer carton packaging to protect from light.

Keep out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the packaging after “Do not use

after” or “EXP.” The expiry date refers to the last day of that month.

Do not throw away any medicine via wastewater or household waste. Ask your pharmacist how

dispose

medicines

longer

required.

These

measures

will

help

protect

environment.

6.

CONTENTS OF THE PACK AND OTHER INFORMATION

What <INVENTED NAME> contains

The active substance is dienogest. Each tablet contains 2 mg dienogest.

other

ingredients

lactose

monohydrate,

maize

starch,

povidone

vegetal

magnesium stearate.

What <INVENTED NAME> looks like and contents of the pack

<INVENTED NAME> tablets are round, white tablets with a diameter of 5 mm.

They are supplied in a blister pack containing 28 tablets.

Boxes contain blister packs with

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

arketing Authorisation Holder

<to be completed nationally>

Manufacturer

<to be completed nationally>

information

about

this

medicine,

please

contact

local

representative

Marketing Authorisation Holder:

This medicinal product is authorised in the Member States of the EEA under the following

names:

This leaflet was last approved in

2018-12-16

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Dienogest León Farma 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

Tablet

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

Posology:

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

food.

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

endometriosis.

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.

barrier method).

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

Paediatric population:

<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

months

adolescent

women

(12-<18)

with

clinically

suspected

confirmed

endometriosis (see sections 4.4 and 5.1).

Geriatric population:

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:

There

data

suggesting

need

dosage

adjustment

patients

with

renal

impairment.

Method of administration:

For oral use.

4.3 Contraindications

<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

discontinued immediately.

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

to normal

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

Warnings

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

<INVENTED

NAME>

although

warnings

precautions

based

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).

Circulatory disorders

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

progestogen-only preparations.

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.

Tumours

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

<INVENTED NAME>.

Osteoporosis

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%

(n=60).

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.

Other conditions

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.

Dienogest

generally

does

appear

affect

blood

pressure

normotensive

women.

However,

sustained

clinically

significant

hypertension

develops

during

<INVENTED NAME>, it is advisable to withdraw <INVENTED NAME> and treat the

hypertension.

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

more

likely

ectopic

than

pregnancies

among

users

combined

oral

contraceptives.

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.

Lactose

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

potential interactions.

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-

induction), e.g.:

phenytoin,

barbiturates,

primidone,

carbamazepine,

rifampicin,

possibly

also

oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing St. John’s wort

Hypericum perforatum).

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

of dienogest.

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-

fold.

Effects of dienogest 2mg on other medication

Based on

in vitro

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

Laboratory tests

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

Pregnancy

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.

Lactation

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.

decision

must

made

whether

discontinue

breast-feeding

abstain

from

<INVENTED NAME> therapy taking into account the benefit of breast-feeding for the child

and the benefit of therapy for the woman.

Fertility

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

containing dienogest.

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 %).

addition,

majority

patients

treated

with

dienogest

experience

changes

their

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).

frequencies

adverse

drug

reactions

(ADRs)

MedDRA

system

organ

classes

(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

Common

Uncommon

Blood

and

lymphatic

system

disorders

anemia

Metabolism

and

nutrition

disorders

weight increase

weight decrease

increased appetite

Psychiatric disorders

depressed mood

sleep disorder

nervousness

loss of libido

altered mood

anxiety

depression

mood swings

Nervous system disorders

headache

migraine

autonomic nervous system imbalance

disturbance in attention

Eye disorders

dry eye

Ear and labyrinth disorders

tinnitus

Cardiac disorders

unspecific

circulatory

system

disorder palpitations

Vascular disorders

hypotension

Respiratory,

thoracic

and

mediastinal disorders

dyspnoea

Gastrointestinal disorders

nausea

abdominal pain

flatulence

diarrhoea

constipation

abdominal discomfortgastrointestinal

System Organ Class

Common

Uncommon

abdominal distension

vomiting

inflammation

gingivitis

Skin

and

subcutaneous

tissue

disorders

acne

alopecia

dry skin

hyperhidrosis

pruritus

hirsutism

onychoclasis

dandruff

dermatitis

abnormal hair growth

photosensitivity

reaction

pigmentation disorder

Musculoskeletal

and

connective

tissue disorders

back pain

bone pain

muscle spasms

pain in extremity

heaviness in extremities

Renal and urinary disorders

urinary tract infection

Reproductive system and breast

disorders

breast discomfort

ovarian cyst

hot flushes

uterine

vaginal

bleeding

including

spotting

vaginal candidiasis

vulvovaginal dryness

genital discharge

pelvic pain

atrophic vulvovaginitis

breast mass

fibrocystic breast disease

breast induration

General

disorders

and

administration site conditions

asthenic

conditions

irritability

Oedema

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

4.4).

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.

4.9 Overdose

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

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

receptor

human

uterus

with

only

relative

affinity

progesterone. Despite its low affinity to the progesterone receptor, dienogest has a strong

progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid or

glucocorticoid activity

in vivo

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

endometriotic lesions.

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

Absorption

Orally

administered

dienogest

rapidly

almost

completely

absorbed.

Peak

serum

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.

Distribution

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.

Metabolism

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

studies,

CYP3A4

major

enzyme

involved

metabolism

dienogest.

metabolites are excreted very quickly so that in plasma unchanged dienogest is the dominating

fraction.

The metabolic clearance rate from serum Cl/F is 64 ml/min.

Elimination

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

half-life

urinary

metabolites

excretion

hours.

Following

oral

administration

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.

Steady-state conditions

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

Lactose monohydrate

Magnesium stearate

Maize starch

Povidone

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store in the

outer carton

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

Pack sizes:

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

requirements

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

2018-12-16

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