Endofemine 2 mg Tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Produktens egenskaper Produktens egenskaper (SPC)

15-03-2019

Aktiva substanser:
dienogest
Tillgänglig från:
Mylan AB
ATC-kod:
G03DB08
INN (International namn):
dienogest
Dos:
2 mg
Läkemedelsform:
Tablett
Sammansättning:
dienogest 2 mg Aktiv substans; laktosmonohydrat Hjälpämne
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:
Avregistrerad
Godkännandenummer:
57386
Tillstånd datum:
2019-03-15

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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

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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