Reasons for adding or updating:

• Change to section 4.2 - Posology and method of administration

Date of revision of text on the SPC: 22-Nov-2016

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Peri-menopause claim was removed in 2014 section 4.2 still contained information related to taking the product if having regular periods.  Information updated.

Reasons for adding or updating:

• Change to section 7 - Marketing authorisation holder
• Change to section 8 - Marketing authorisation number(s)

Date of revision of text on the SPC: 26-Aug-2016

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Change of Ownership from BGP Products Ltd, Abbott House, Maidenhead (PL 43900/0038) to Mylan Products Ltd, Potters Bar (PL 46302/0036)

Reasons for adding or updating:

• Change to section 6.1 - List of excipients

Date of revision of text on the SPC: 25-Apr-2016

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Correction to E no for iron oxide for tablet coating

Reasons for adding or updating:

• Change to section 6.4 - Special precautions for storage

Date of revision of text on the SPC: 25-Apr-2016

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Storage conditions changed to:  This medicinal product does not require any special storage conditions.

Reasons for adding or updating:

• Change to section 4.4 - Special warnings and precautions for use
• Change to section 4.8 - Undesirable effects

Date of revision of text on the SPC: 13-Apr-2016

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Changes to warnings and incidence levels related to ovarian cancer updated.

Reasons for adding or updating:

• Change to section 5.2 - Pharmacokinetic properties

Date of revision of text on the SPC: 12-Apr-2016

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Correction to absorption data (in table) for oestrogen 2mg.

Reasons for adding or updating:

• Correction of spelling/typing errors

Date of revision of text on the SPC: 14-Apr-2015

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Black Triangle (CHM): NO

Reasons for adding or updating:

• Correction of spelling/typing errors

Date of revision of text on the SPC: 15-Apr-2015

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Reasons for adding or updating:

• Change to section 7 - Marketing authorisation holder
• Change to section 8 - Marketing authorisation number(s)
• Change to section 10 - Date of revision of the text
• Company name change or merger

Date of revision of text on the SPC: 14-Apr-2015

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 Due to Change of Ownership

• In section 7 ( MA Holder ) has changed from  Abbott Healthcare Products Limited/Abbott Laboratories  to BGP Products Ltd
• In section 8 ( MA number ) has changed from PL00512/0113 to PL 43900/0038
• In section 10 ( Date of revision of text) has been updated to 14/04/15

Reasons for adding or updating:

• Change to section 2 - Qualitative and quantitative composition
• Change to section 4.3 - Contraindications
• Change to section 4.8 - Undesirable effects
• Change to section 4.9 - Overdose

Date of revision of text on the SPC: 06-Jan-2015

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All changes (new text, moved and  deleted text shown in red)

Section 2 added:

Excipient with known effect: lactose monohydrate

Section 3
Added text in red:

-      Known or suspected progestogen-dependent neoplasms (e.g. meningioma);

Moved text to end of list:

-      Known hypersensitivity to the active substances or to any of the excipients.

Section 4.8

Changes in red text:

Undesirable effects reported in clinical trials and in postmarketing experience are the following:

The most commonly reported adverse drug reactions of patients treated with estradiol/dydrogesterone in clinical trials are headache, abdominal pain, breast pain/tenderness and back pain.

 

The following undesirable effects have been observed with the frequencies indicated below during clinical trials (n=4929):

In the ADR table - 
Deleted: Very Rare column and all side effects
Added: Very Common column

MedDRA system organ class			Very common > 1/10			Common >1/100, <1/10	Uncommon >1/1,000, <1/100	Rare >1/10,000, <1/1,000	Very rare <1/10,000 incl. isolated reports
Infections and infestations						Vaginal candidiasis	Cystitis-like syndrome Vaginal candidiasis
Neoplasms benign, malignant and unspecified							Increase in size of leiomyoma
Blood and the lymphatic system disorders									Haemolytic anaemia
Immune system disorders							Hypersensitivity		Hypersensitivity
Psychiatric disorders						Depression, Nervousness	Depression, Change in Influence on libido, Nervousness
Nervous system disorders			Headache			Headache, Migraine, Dizziness	Dizziness		Chorea
Eye disorders								Intolerance to contact lenses, Steepening of corneal curvature
Cardiac disorders								Myocardial infarction	Myocardial infarction
Vascular disorders							Hypertension, Peripheral vascular disease, Varicose vein, Venous thromboembolism		Stroke
Gastrointestinal disorders			Abdominal pain			Nausea, Vomiting, Abdominal pain, Flatulence	Dyspepsia		Vomiting
Hepatobiliary disorders							Abnormal hepatic function, occasionally with jaundice asthenia or malaise, and abdominal pain, Gall bladder disorder disease	Alterations in liver function, sometimes with Asthenia or Malaise, Jaundice and Abdominal pain
Skin and subcutaneous tissue disorders						Allergic skin reactions (e.g. rash, urticaria, pruritus)	Allergic skin reactions, Rash, Urticaria, Pruritus	Angioedema , Vascular purpura	Chloasma or melasma, which may persist when drug is discontinued, Erythema multiforme, Erythema nodosum, Vascular purpura, Angioedema
Musculoskeletal and connective tissue disorders			Back pain			Leg cramps	Back pain
Reproductive system and breast disorders			Breast pain/tenderness			Breast pain/tenderness, Metrorrhagia and postmenopausal spotting, Menstrual disorders (including postmenopausal spotting, metrorrhagia, menorrhagia, oligo- /amenorrhoea, irregular menstruation, dysmenorrhoea),Pelvic pain, Cervical discharge	Change in cervical erosion, Change in cervical secretion, Dysmenorrhoea, Menorrhagia Breast enlargement, Premenstrual syndrome	Breast enlargement, Premenstrual-like symptoms
Congenital and familial/genetic disorders									Aggravation of porphyria
General disorders and administration site reactions						Asthenic conditions (asthenia, fatigue, malaise), Peripheral oedema AstheniaAsthenia	Peripheral oedema
Investigations				Increased weight/decrease in weight			Decreased weight

...

 

US WHI studies - additional risk of breast cancer after 5 years’ use

Age range (years)	Incidence per 1000 women in placebo arm over 5 years	Risk ratio & 95%CI	Additional cases per 1000 HRT users over 5 years (95%CI)
CEE oestrogen-only
50-79	21	0.8 (0.7 – 1.0)	-4 (-6 – 0)*2
CEE+MPA oestrogen & progestagen‡
50-79	17 14	1.2 (1.0 – 1.5)	+4 (0 – 9)

...

Other adverse reactions have been reported in association with oestrogen/progestogen

treatment (including estradiol/dydrogesterone):

 

Neoplasms benign, malignant and unspecified:

Oestrogen dependent neoplasms both benign and malignant, e.g. endometrial cancer, ovarian cancer. Increase in size of progestogen dependent neoplasms, e.g. meningioma.

 

Blood and lymphatic system disorders:

Haemolytic anaemia

 

Immune system disorders:

Systemic lupus erythematosus

 

Metabolism and nutrition disorders:

Hypertriglyceridemia

 

Nervous system disorders:

Probable dementia over the age of 65(see section 4.4), chorea, exacerbation of epilepsy

 

Eye disorders:

Steepening of corneal curvature, contact lenses intolerance

 

Reproductive system and breast disorders:

Fibrocystic breast changes

 

Vascular disorders:

Arterial thromboembolism

 

Gastrointestinal disorders:

Pancreatitis (in women with pre-existing hypertriglyceridemia)

 

Skin and subcutaneous tissue disorders:

Erythema multiforme, erythema nodosum, chloasma or melasma, which may persist

when drug is discontinued.

 

Musculoskeletal and connective tissue disorders:

Leg cramps

Investigations:

Total thyroid hormones increased

 

Renal and urinary disorders:

Urinary incontinence

 

Reproductive system and breast disorders:

Fibrocystic breast disease, uterine cervical erosion

 

Congenital, familial and genetic disorders:

Aggravated porphyria

 

Investigations:

Total thyroid hormones increased

Section 4.9

Adeed text in red:
Both oestradiol and dydrogesterone are substances with low toxicity. Theoretically Symptoms such as nausea, vomiting, breast tenderness sleepiness, dizziness, abdominal pain, drowsiness/fatigue, and withdrawal bleeding could occur in cases of overdosing. It is unlikely that any specific or symptomatic treatment will be necessary.

Reasons for adding or updating:

• Change to section 4.2 - Posology and method of administration
• Change to section 4.3 - Contraindications
• Change to section 4.4 - Special warnings and precautions for use
• Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
• Change to section 4.6 - Fertility, pregnancy and lactation
• Change to section 4.8 - Undesirable effects

Date of revision of text on the SPC: 05-Oct-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



New text added is in green.

Section 4.2 add:

Paediatric population:

There is no relevant indication for the use of Femoston in the paediatric population.

Section 4.3 add:

-      Known or suspected progestogen-dependent neoplasms;

Section 4.4 add:

Oestrogen-only therapy

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of oestrogen-progestogen combinations (see section 4.8).

 

The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.

 

HRT, especially oestrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Section 4.5 add:

No interaction studies have been performed.

 

The efficacy of oestrogens and progestogens might be impaired:

The metabolism of oestrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochromethe P450 enzymes 2B6, 3A4, 3A5, 3A7, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamezapin) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors of CYP450 3A4, A5, A7, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John’s Wwort (Hypericum perforatum) may induce the metabolism of oestrogens and progestagens via the CYP450 3A4 pathway.

Clinically an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.

 

Oestrogens might interfere with the metabolism of other drugs:

Oestrogens per se may inhibit CYP450 drug-metabolising enzymes via competitive inhibition. This is in particular to be considered for substrates with a narrow therapeutic index, such as:

- tacrolimus and cyclosporine A (CYP450 3A4, 3A3)

- fentanyl (CYP450 3A4)

- theophylline (CYP450 1A2).

 

Clinically this may lead to an increased plasma level of the affected substances up to toxic concentrations. Thus, careful drug monitoring for an extended period of time might be indicated and a dosage decrease of tacrolimus, fentanyl, cyclosporin A and theophylline may be necessary.

Section 4.6 add:

Pregnancy:

Femoston is not indicated during pregnancy. If pregnancy occurs during medication with Femoston, treatment should be withdrawn immediately.

Data based on an assumed large number of exposed pregnancies indicate no adverse effects of dydrogesterone on the foetus.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of oestrogens and progestagens indicate no teratogenic or foetotoxic effect.

There are no adequate data from the use of estradiol/dydrogesterone in pregnant women.

 

Lactation:

Femoston is not indicated during lactation.

Section 4.8 add:

                                                                                                                      Very Rare:

Immune system disorders

Hypersensitivity

    Common                                                                 Uncommon

Breast pain/tenderness, Metrorrhagia and postmenopausal spotting,Breakthrough bleeding and spotting, Pelvic pain

Change in cervical erosion, Change in cervical secretion, Dysmenorrhoea, Menorrhagia, Metrorrhagia

Other adverse reactions have been reported in association with oestrogen/progestogen

treatment:

 

Neoplasms benign, malignant and unspecified:

Oestrogen dependent neoplasms both benign and malignant, e.g. endometrial cancer, ovarian cancer. Increase in size of progestogen dependent neoplasms, e.g. meningioma.

 

Immune system disorders:

Systemic lupus erythematosus

 

Metabolism and nutrition disorders:

Hypertriglyceridemia

 

Nervous system disorders:

Probable dementia, exacerbation of epilepsy

 

Reproductive system and breast disorders:

Fibrocystic breast changes

 

Vascular disorders:

Arterial thromboembolism

 

Gastrointestinal disorders:

Pancreatitis (in women with pre-existing hypertriglyceridemia)

 

Investigations:

Total thyroid hormones increased

 

Renal and urinary disorders:

Urinary incontinence

 

Reasons for adding or updating:

• Change to section 4.1 - Therapeutic indications

Date of revision of text on the SPC: 19-Sep-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Update to Section 4.1 Indication:

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in  peri and postmenopausal women at least 6 months since last menses.

Reasons for adding or updating:

• Change to section 4.8 - Undesirable effects - how to report a side effect
• Change to section 7 - Marketing authorisation holder
• Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 11-Aug-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.8 how to report side effects added:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Section 7
change of MAH Address to:

 

Abbott Healthcare Products Limited

Abbott House,

Vanwall Business Park,

Vanwall Road, Maidenhead,

SL6 4XE,

 

UK

Section 10 updated revision date: 11 August 2014

Reasons for adding or updating:

• Change to section 5.2 - Pharmacokinetic properties
• Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 03-Mar-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Complete re-write of seciton 5.2

Previous text:

Oestradiol

Orally administered oestradiol, comprising particles whose size has been reduced to less than 5 μm, is quickly and efficiently absorbed from the gastrointestinal tract. The primary unconjugated and conjugated metabolites are oestrone and oestrone sulphate. These metabolites can contribute to the oestrogen effect, both directly and after conversion to oestradiol. Oestrogens are excreted in the bile and reabsorbed from the intestine. During this enterohepatic cycle the oestrogens are broken down. Oestrogens are excreted in the urine as biologically inactive glucuronide and sulphate compounds (90 to 95%), or in the faeces (5 to 10%), mostly unconjugated. Oestrogens are excreted in mothers' milk.

During the administration of oral oestradiol to post-menopausal women at 2 mg once a day the C_average is 58 pg/ml, the C_min is 44 pg/ml and the C_max is 93 pg/ml. The E1/E2 (Oestrone/Oestradiol) ratio is 5.8.

 

Dydrogesterone

After oral administration of labelled dydrogesterone, on average 63% of the dose is excreted into the urine. Within 72 hours, excretion is complete.

 

In man, dydrogesterone is completely metabolised. The main metabolite of dydrogesterone is 20α-dihydrodydrogesterone (DHD) and is present in the urine predominantly as the glucoronic acid conjugate. A common feature of all metabolites characterised is the retention of the 4,6 diene-3-one configuration of the parent compound and the absence of 17α-hydroxylation. This explains the absence of oestrogenic and androgenic activity.

 

After oral administration of dydrogesterone, plasma concentrations of DHD are substantially higher as compared to the parent drug. The AUC and C_max ratios of DHD to dydrogesterone are in the order of 40 and 25, respectively. Dydrogesterone is rapidly absorbed. The T_max values of dydrogesterone and DHD vary between 0.5 and 2.5 hours.

 

Mean terminal half lives of dydrogesterone and DHD vary between 5 to 7 and 14 to 17 hours, respectively.

The dihydrodydrogesterone C_average is 13 ng/ml, the C_min is 4.1 ng/ml and the C_max is 63 ng/ml. The dydrogesterone C_average is 0.38 ng/ml the C_min is <0.1 ng/ml and the C_max is 2.5 ng/ml.

Dydrogesterone is not excreted in urine as pregnanediol, like progesterone. Analysis of endogenous progesterone production based on pregnanediol excretion therefore remains possible.

New text:

Estradiol

 

• Absorption

Absorption of estradiol is dependent on the particle size: micronized estradiol is readily absorbed from the gastrointestinal tract.

 

The following table provides the mean steady state pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for each dose of micronized estradiol. Data is presented as mean (SD).

 

Estradiol 1 mg
Parameters	E2	E1	Parameters	E1S
Cmax (pg/mL)	71 (36)	310 (99)	Cmax (ng/mL)	9.3 (3.9)
Cmin (pg/mL)	18.6 (9.4)	114 (50)	Cmin (ng/mL)	2.099 (1.340)
Cav (pg/mL)	30.1 (11.0)	194 (72)	Cav (ng/mL)	4.695 (2.350)
AUC0-24 (pg.h/mL)	725 (270)	4767 (1857)	AUC0-24 (ng.h/mL)	112.7 (55.1)

 

 

• Distribution

Oestrogens can be found either unbound or bound. About 98- 99% of the estradiol dose binds to plasma proteins, from which about 30-52% to albumin and about 46-69% to the sex hormone-binding globulin (SHBG).

 

• Metabolism

Following oral administration, estradiol is extensively metabolised. The major unconjugated and conjugated metabolites are estrone and estrone sulphate. These metabolites can contribute to the oestrogen activity, either directly or after conversion to estradiol. Estrone sulphate may undergo enterohepatic circulation.

 

• Elimination

In urine, the major compounds are the glucuronides of estrone and estradiol. The elimination half-life is between 10-16 h.

Oestrogens are secreted in the milk of nursing mothers.

 

• Dose and time dependencies

Following daily oral administration of Femoston, estradiol concentrations reached a steady-state after about five days.

Generally, steady state concentrations appeared to be reached for within 8 to 11 days of dosing.

 

 

Dydrogesterone:

 

• Absorption

Following oral administration, dydrogesterone is rapidly absorbed with a Tmax between 0.5 and 2.5 hours. The absolute bioavailability of dydrogesterone (oral 20 mg dose versus 7.8 mg intravenous infusion) is 28 %.

 

The following table provide the mean steady state pharmacokinetic parameters of

dydrogesterone (D) and dihydrodydrogesterone (DHD). Data is presented as mean (SD).

 

Dydrogesterone 10 mg
Parameters	D	DHD
Cmax (ng/mL)	2.54 (1.80)	62.50 (33.10)
Cmin (ng/mL)	0.13 (0.07)	3.70 (1.67)
Cav (ng/mL)	0.42 (0.25)	13.04 (4.77)
AUC0-t (ng.h/mL)	9.14 (6.43)	311.17 (114.35)

 

 

• Distribution

After intravenous administration of dydrogesterone the steady-state volume of distribution is approximately 1400 L. Dydrogesterone and DHD are more than 90% bound to plasma proteins.

 

• Metabolism

Following oral administration, dydrogesterone is rapidly metabolised to DHD. The levels of the main active metabolite 20 α-dihydrodydrogesterone (DHD) peak about 1.5 hours post dose. The plasma levels of DHD are substantially higher as compared to the parent drug. The AUC and Cmax ratios of DHD to dydrogesterone are in the order of 40 and 25, respectively. Mean terminal half lives of dydrogesterone and DHD vary between 5 to 7 and 14 to 17 hours, respectively. A common feature of all metabolites characterised is the retention of the 4,6 diene-3-one configuration of the parent compound and the absence of 17α- hydroxylation. This explains the lack of oestrogenic and androgenic effects of dydrogesterone.

 

• Elimination

After oral administration of labelled dydrogesterone, on average 63% of the dose is excreted into the urine. Total plasma clearance is 6.4 L/min. Within 72 hours excretion is complete. DHD is present in the urine predominantly as the glucuronic acid conjugate.

 

• Dose and time dependencies

The single and multiple dose pharmacokinetics are linear in the oral dose range 2.5 to 10 mg. Comparison of the single and multiple dose kinetics shows that the pharmacokinetics of dydrogesterone and DHD are not changed as a result of repeated dosing. Steady state was reached after 3 days of treatment.

 

Reasons for adding or updating:

• Change to section 5.3 - Preclinical safety data
• Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 28-Feb-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Update to section 5.3 (red is new text):

Supraphysiologically high doses (prolonged overdoses) of oestradiol have been associated with the induction of tumours in oestrogen-dependent target organs for all rodent species tested. The changes observed with dydrogesterone in animal toxicity studies are characteristic for progesterone-like compounds. In-vitro and in-vivo data gave no indications of mutagenic effects of dydrogesterone. In long-term studies, doses administered to rats and mice were sufficient to produce hormone-mediated changes, but did not provide tumorogenic potential. There are no preclinical safety data of relevance to the prescriber in the target population that are additional to those already included in other sections of the Summary of Product Characteristics (SmPC).

Section 10 updated to 28 February 2014.

Reasons for adding or updating:

• Change to section 5.1 - Pharmacodynamic properties

Date of revision of text on the SPC: 11-Jun-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 5.1 Pharmacodynamic Properties

Dydrogesterone

Previously:

Dydrogesterone is an orally-active progestagen.  As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer.  The addition of a progestagen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Now:

Dydrogesterone is an orally-active progestagen having an activity comparable to parenterally administered progesterone.  As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer.  The addition of a progestagen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Section 10 Date of Revision of the Text

Was 16 January 2012 and is now 11 June 2013.

Reasons for adding or updating:

• Change to section 3 - Pharmaceutical form
• Change to section 4.1 - Therapeutic indications
• Change to section 4.2 - Posology and method of administration
• Change to section 4.3 - Contraindications
• Change to section 4.4 - Special warnings and precautions for Use
• Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
• Change to section 4.6 - Pregnancy and Lactation
• Change to section 4.8 - Undesirable Effects
• Change to section 4.9 - Overdose
• Change to section 5.1 - Pharmacodynamic Properties
• Change to section 5.2 - Pharmacokinetic Properties
• Change to section 5.3 - Preclinical Safety Data
• Change to section 6.1 - List of Excipients

Date of revision of text on the SPC: 16-Jan-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

SPC section changes:
3, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.8, 4.9, 5.1, 5.2, 5.3 & 6.1.

PRESENT and PROPOSED SPCs:

PRESENT:

Summary of Product Characteristics

 

1.         NAME OF THE MEDICINAL PRODUCT

 

Femoston^® 2/10 mg Film-coated tablets

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each tablet contains 2 mg estradiol (as hemihydrate) or a combination of 2 mg estradiol (as hemihydrate) and 10 mg dydrogesterone.

 

For excipients see 6.1

 

3.         PHARMACEUTICAL FORM

 

Film-coated tablets

Estradiol only tablets: Round, biconvex, brick-red film-coated tablets with inscriptions ‘ ’ and '379'.

Estradiol/dydrogesterone combination tablets: Round, biconvex, yellow film-coated tablets with inscriptions ‘ ’ and '379'.

 

4.         CLINICAL PARTICULARS

 

4.1.            Therapeutic Indications

 

Hormone replacement therapy (HRT) for estrogen deficiency symptoms in peri and postmenopausal women.

 

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.

 

(See also section 4.4)

 

The experience in treating women older than 65 years is limited.

 

4.2.            Posology and method of administration

 

Femoston 1/10, and Femoston 2/10, are continuous sequential hormone replacement therapy. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.

 

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used.

In general, treatment should start with Femoston 1/10. Depending on the clinical response, the dosage can afterwards be adjusted to individual need. If the complaints linked to estrogen deficiency are not ameliorated the dosage can be increased by using Femoston 2/10.

 

Starting Femoston

In women who are not taking hormone replacement therapy and who are amenorrhoeic, or women who switch from a continuous combined hormone replacement therapy, treatment may be started on any convenient day. In women transferring from a cyclic or continuous sequential HRT regimen, treatment should begin the day following completion of the prior regimen. If the patient has regular menstruation periods, treatment is started within five days of the start of bleeding.

 

 

Administration

For the first 14 days during a 28-cycle, one tablet containing estradiol is taken daily; during the following 14 days one tablet containing estradiol and dydrogesterone is taken.

 

After a cycle of 28 days, on the 29th day, a new 28-day cycle begins. This means that the treatment should be taken continuously without a break between packs. Femoston can be taken with or without food.

 

The days of the week are printed on the back of the blister strips. Firstly the tablets from the part marked with arrow 1 should be taken, then all the tablets from the part marked with arrow 2 should be taken.

 

If a dose has been forgotten, it should be taken as soon as possible. When more than 12 hours have elapsed, it is recommended to continue with the next dose without taking the forgotten tablet. The likelihood of breakthrough bleeding or spotting may be increased.

 

4.3.      Contraindications

 

Known, past or suspected breast cancer;
Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer);

Undiagnosed genital bleeding;

Untreated endometrial hyperplasia;

Previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary embolism);

Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction);

Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal;

Known hypersensitivity to the active substances or to any of the excipients;

Porphyria.

 

4.4              Special warnings and precautions for use

 

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life.  In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

Medical examination/follow up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see ‘breast cancer’ below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Femoston, in particular:

·       Leiomyoma (uterine fibroids) or endometriosis

·       A history of, or risk factors for, thromboembolic disorders (see below)

·       Risk factors for estrogen dependent tumours, e.g. 1^st degree heredity for breast cancer

·       Hypertension

·       Liver disorders (e.g. liver adenoma)

·       Diabetes mellitus with or without vascular involvement

·       Cholelithiasis

·       Migraine or (severe) headache

·       Systemic lupus erythematosus

·       A history of endometrial hyperplasia (see below)

·       Epilepsy

·       Asthma

·       Otosclerosis

 

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in cases where a contra-indication is discovered and in the following situations:

·       Jaundice or deterioration in liver function

·       Significant increase in blood pressure

·       New onset of migraine-type headache

·       Pregnancy

Endometrial hyperplasia

The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen for at least 12 days of the cycle in non-hysterectomised women greatly reduces this risk.

Break-through bleeding and spotting may occur during the first months of treatment.. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Breast cancer

A randomised placebo-controlled trial, the Womens Health Initiative study (WHI) and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestagen combinations or tibolone for HRT for several years (see Section 4.8).

For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Venous thromboembolism

HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two-to threefold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

·       Generally recognised risk factors for VTE include a personal or family history, severe obesity (BMI>30 kg/m²) and systemic lupus erythematosus (SLE).  There is no consensus about the possible role of varicose veins in VTE.

·       Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

·       The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery.  Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.

·       If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnea).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials to date examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer

Long-term (at least 5 to 10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long term use of combined HRT confers a different risk than estrogen-only products.

Other conditions

·            Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Femoston is increased.

·            Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

·            Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex- ­hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

·            There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65.  It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

·            Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

·            Women who may be at risk of pregnancy should be advised to adhere to non-hormonal contraceptive methods

 

4.5.            Interaction with other medicinal products and other forms of Interaction

 

-     The metabolism of estrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (eg. phenobarbital, phenytoin, carbamezapine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

-     Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.

-     Herbal preparations containing St John’s wort (Hypericum perforatum) may induce the metabolism of estrogens and progestagens.

-     Clinically an increased metabolism of estrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.

 

4.6.      Pregnancy and lactation

 

Pregnancy:

Femoston is not indicated during pregnancy. If pregnancy occurs during medication with Femoston, treatment should be withdrawn immediately.

Clinically, data based on a large number of exposed pregnancies indicate no adverse effects of dydrogesterone on the foetus.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of estrogens and progestagens indicate no teratogenic or foetotoxic effect.

 

Lactation:

Femoston is not indicated during lactation.

 

4.7.      Effects on ability to drive and use machines

 

Femoston does not affect the ability to drive or use machines.

 

 

4.8       Undesirable Effects

Undesirable effects reported in clinical trials and in postmarketing experience are the following:

 

MedDRA system organ class	Common >1/100, <1/10	Uncommon >1/1,000, <1/100	Rare >1/10,000, <1/1,000	Very rare <1/10,000 incl. isolated reports
Infections and infestations		Cystitis-like syndrome, Vaginal candidiasis
Neoplasms benign, malignant and unspecified		Increase in size of leiomyoma
Blood and the lymphatic system disorders				Haemolytic anaemia
Immune system disorders				Hypersensitivity reactions
Psychiatric disorders		Depression, Change in libido, Nervousness
Nervous system disorders	Headache, Migraine	Dizziness		Chorea
Eye disorders			Intolerance to contact lenses, Steepening of corneal curvature
Cardiac disorders				Myocardial infarction
Vascular disorders		Hypertension, Peripheral vascular disease, Varicose vein, Venous thromboembolism **		Stroke
Gastrointestinal disorders	Nausea, Abdominal pain, Flatulence	Dyspepsia		Vomiting
Hepatobiliary disorders		Gall bladder disease	Alterations in liver function, sometimes with Asthenia or Malaise, Jaundice and Abdominal pain
Skin and subcutaneous tissue disorders		Allergic skin reactions, Rash, Urticaria, Pruritus		Chloasma or melasma, which may persist when drug is discontinued, Erythema multiforme, Erythema nodosum, Vascular purpura, Angioedema
Musculoskeletal and connective tissue disorders	Leg cramps	Back pain
Reproductive system and breast disorders	Breast pain/tenderness, Metrorrhagia and postmenopausal spotting (breakthrough bleeding), Pelvic pain	Uterine cervical erosion, Change in cervical secretion, Dysmenorrhoea, Menorrhagia	Breast enlargement, Premenstrual-like symptoms
Congenital and familial/genetic disorders				Aggravation of porphyria
General disorders and administration site reactions	Asthenia	Peripheral oedema
Investigations	Increase/decrease in weight

** see below for further information

Breast Cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women’s Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For estrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68). 

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trials are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

-     For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

-     For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be

-     For users of estrogen-only replacement therapy

·            between 0 and 3 (best estimate = 1.5) for 5 years’ use

·            between 3 and 7 (best estimate = 5) for 10 years’ use. 

 

-     For users of estrogen plus progestagen combined HRT,

·            between 5 and 7 (best estimate = 6) for 5 years’ use

·            between 18 and 20 (best estimate = 19) for 10 years’ use.

 

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years. 

According to calculations from the trial data, it is estimated that:

-     For 1000 women in the placebo group,

·         about 16 cases of invasive breast cancer would be diagnosed in 5 years.

 

-     For 1000 women who used estrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be

·         between 0 and 9 (best estimate = 4) for 5 years’ use.

 

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).’

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2-to 12-fold greater compared with non-users.  Adding a progestagen to estrogen-only therapy greatly reduces this increased risk.

Other adverse reactions reported in association with estrogen/progestagen treatment:

Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use.

Estrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer, ovarian cancer.

Systemic lupus erythematosus.

Probable dementia (see section 4.4).

Exacerbation of epilepsy.

 

4.9.      Overdose

 

Both estradiol and dydrogesterone are substances with low toxicity. Theoretically, symptoms such as nausea, vomiting, sleepiness and dizziness could occur in cases of overdosing. It is unlikely that any specific or symptomatic treatment will be necessary.

Aforementioned information is applicable for overdosing by children also.

 

 

5.         Pharmacological Properties

 

5.1.      Pharmacodynamic Properties

 

The ATC code is G03FB08. (Estrogens: urogenital system and sex hormones)

Sequential hormone replacement therapy (combined estradiol and dydrogesterone).

 

Estradiol

The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.

 

Dydrogesterone

Dydrogesterone is an orally-active progestagen. The addition of a progestagen greatly reduces the estrogen-induced risk of endometrial hyperplasia and cancer in non-hysterectomised women, by reducing the growth of the endometrium.

 

Clinical trial Information

·         Relief of estrogen-deficiency symptoms and bleeding patterns.

-          Relief of menopausal symptoms was achieved during the first few weeks of

         treatment.

-          Regular withdrawal bleeding with Femoston 1/10 occurred in approximately 75-80% of women with a mean duration of 5 days. Withdrawal bleeding usually started on the day of the last pill of the progestagen phase. Break-through bleeding and/or spotting occurred in approximately 10% of the women; amenorrhoea (no bleeding or spotting) occurred in 21-25% of the women for months 10 to 12 of treatment.

-     With Femoston 2/10, approximately 90% of women had regular withdrawal bleeding. The start day and duration of bleeding, and the number of women with intermittent bleeding was the same as with Femoston 1/10, amenorrhoea occurred in 7-11% of the women for months 10 to 12 of treatments.

 

·         Prevention of osteoporosis

-          Estrogen deficiency at menopause is associated with an increasing bone

      turnover and decline in bone mass. The effect of estrogens on the bone mineral

density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

-     Evidence from the WHI trial and meta-analysed trials shows that current use of

HRT, alone or in combination with a progestagen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

-         After two years of treatment with Femoston 2/10, the increase in lumbar spine bone mineral density (BMD) was 6.7% ± 3.9% (mean ± SD). The percentage of women who maintained or gained BMD in lumbar zone during treatment was 94.5%. For Femoston 1/10 the increase in lumbar spine BMD was 5.2% ± 3.8% (mean ± SD), and the percentage of women with no change or an increase in lumbar spine BMD was 93%.

-     Femoston also had an effect on hip BMD. The increase after two years of treatment with 1mg estradiol was 2.7% ± 4.2% (mean ± SD) at femoral neck, 3.5% ± 5.0% (mean ± SD) at trochanter and 2.7%± 6.7% (mean ± SD) at Wards triangle. After two years of treatment with 2mg estradiol these figures were respectively, 2.6% ± 5.0%; 4.6% ± 5.0% and 4.1% ± 7.4%. The percentage of women who maintained or gained BMD in the 3 hip areas after treatment with 1mg estradiol was 67-78% and 71-88% after treatment with 2mg estradiol.

 

5.2.            Pharmacokinetic Properties

 

Estradiol

Orally administered estradiol, comprising particles whose size has been reduced to less than 5 µm, is quickly and efficiently absorbed from the gastrointestinal tract. The primary unconjugated and conjugated metabolites are estrone and estrone sulphate. These metabolites can contribute to the estrogen effect, both directly and after conversion to estradiol. Estrogens are excreted in the bile and reabsorbed from the intestine. During this enterohepatic cycle the estrogens are broken down. Estrogens are excreted in the urine as biologically inactive glucuronide and sulphate compounds (90 to 95%), or in the faeces (5 to 10%), mostly unconjugated. Estrogens are excreted in mothers' milk.

During the administration of oral estradiol to post-menopausal women at 2 mg once a day the C_average is 58 pg/ml, the C_min is 44 pg/ml and the C_max is 93 pg/ml. The E1/E2 (Estrone/Estradiol) ratio is 5.8.

 

Dydrogesterone

After oral administration of labelled dydrogesterone, on average 63% of the dose is excreted into the urine.  Within 72 hours, excretion is complete.

 

In man, dydrogesterone is completely metabolised.  The main metabolite of dydrogesterone is 20a-dihydrodydrogesterone (DHD) and is present in the urine predominantly as the glucoronic acid conjugate.  A common feature of all metabolites characterised is the retention of the 4,6 diene-3-one configuration of the parent compound and the absence of 17a-hydroxylation.  This explains the absence of estrogenic and androgenic activity.

 

After oral administration of dydrogesterone, plasma concentrations of DHD are substantially higher as compared to the parent drug.  The AUC and C_max ratios of DHD to dydrogesterone are in the order of 40 and 25, respectively.  Dydrogesterone is rapidly absorbed.  The T_max values of dydrogesterone and DHD vary between 0.5 and 2.5 hours.

 

Mean terminal half lives of dydrogesterone and DHD vary between 5 to 7 and 14 to 17 hours, respectively.

The dihydrodydrogesterone C_average is 13 ng/ml, the C_min is 4.1 ng/ml and the C_max is 63 ng/ml. The dydrogesterone C_average is 0.38 ng/ml the C_min is <0.1 ng/ml and the C_max is 2.5 ng/ml.

Dydrogesterone is not excreted in urine as pregnanediol, like progesterone.  Analysis of endogenous progesterone production based on pregnanediol excretion therefore remains possible. 

 

5.3.      Preclinical Safety Data

 

Supraphysiologically high doses (prolonged overdoses) of estradiol have been associated with the induction of tumours in estrogen-dependent target organs for all rodent species tested. The changes observed with dydrogesterone in animal toxicity studies are characteristic for progesterone-like compounds. In-vitro and in-vivo data gave no indications of mutagenic effects of dydrogesterone. In long-term studies, doses administered to rats and mice were sufficient to produce hormone-mediated changes, but did not provide tumorogenic potential.

 

 

6.         Pharmaceutical Particulars

 

6.1.            List of Excipients

 

Estradiol only tablets (brick-red):

Tablet core:

Lactose

Hypromellose

Maize starch

Colloidal anhydrous silica

Magnesium stearate

 

Film coat:

Hypromellose

Talc

Macrogol 400

Titanium dioxide E171

Iron oxide red E171

Iron oxide black E172

Iron oxides yellow E172

 

Estradiol/Dydrogesterone tablets (yellow):

Tablet core:

Lactose

Hypromellose

Maize starch

Colloidal anhydrous silica

Magnesium stearate

 

Film coat:

Hypromellose

Talc

Macrogol 400

Titanium dioxide (E171)

Iron oxide yellow (E172)

 

 

6.2.      Incompatibilities

 

Not applicable.

 

6.3.      Shelf life

 

3 years.

 

6.4.      Special precautions for storage

 

Do not store above 30°C.

 

6.5.      Nature and contents of container

 

The tablets are packed in blister strips of 28.  The blister packs are made of PVC/PVdC or PVC film with a covering aluminium foil.  Each carton contains 28 or 84 tablets.

 

6.6.      Instruction for use and handling

 

Not applicable.

 

 

7.         MARKETING AUTHORISATION HOLDER

 

Abbott Healthcare Products Limited

Mansbridge Road

West End

Southampton

SO18 3JD

 

8.         MARKETING AUTHORISATION NUMBER(S)

 

PL 00512/0113

 

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

17 January 1995

 

10.       DATE OF REVISION OF THE TEXT

 

19 April 2011

 

            Legal category

 

POM




PROPOSED:

SUMMARY OF PRODUCT CHARACTERISTICS

 

1. NAME OF THE MEDICINAL PRODUCT

 

Femoston^® 2/10 mg Film-coated tablets

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each tablet contains 2 mg oestradiol (as hemihydrate) or a combination of 2 mg oestradiol (as hemihydrate) and 10 mg dydrogesterone.

 

For a full list of excipients see 6.1

 

 

3. PHARMACEUTICAL FORM

 

Film-coated tablets

 

Oestradiol only tablets: Round, biconvex, brick-red film-coated tablets with inscription '379'.

 

Oestradiol/dydrogesterone combination tablets: Round, biconvex, yellow film-coated tablets with inscription '379'.

 

 

4. CLINICAL PARTICULARS

 

4.1 Therapeutic Indications

 

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in peri and postmenopausal women.

 

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis. (See also section 4.4)

 

The experience in treating women older than 65 years is limited.

 

 

4.2 Posology and method of administration

 

Femoston 1/10, and Femoston 2/10, are continuous sequential hormone replacement therapies.

 

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used.

In general, treatment should start with Femoston 1/10. Depending on the clinical response, the dosage can afterwards be adjusted to individual need. If the complaints linked to oestrogen deficiency are not ameliorated the dosage can be increased by using Femoston 2/10.

 

Starting Femoston

In women who are not taking hormone replacement therapy and who are amenorrhoeic, or women who switch from a continuous combined hormone replacement therapy, treatment may be started on any convenient day. In women transferring from a cyclic or continuous sequential HRT regimen, treatment should begin the day following completion of the prior regimen. If the patient has regular menstruation periods, treatment is started within five days of the start of bleeding.

 

Administration

 

For the first 14 days during a 28-cycle, one tablet containing oestradiol is taken daily; during the following 14 days one tablet containing oestradiol and dydrogesterone is taken.

After a cycle of 28 days, on the 29th day, a new 28-day cycle begins. This means that the treatment should be taken continuously without a break between packs. Femoston can be taken with or without food.

 

The days of the week are printed on the back of the blister strips. Firstly the tablets from the part marked with arrow 1 should be taken, then all the tablets from the part marked with arrow 2 should be taken.

 

If a dose has been forgotten, it should be taken as soon as possible. When more than 12 hours have elapsed, it is recommended to continue with the next dose without taking the forgotten tablet. The likelihood of breakthrough bleeding or spotting may be increased.

 

 

4.3. Contraindications

 

-         Known, past or suspected breast cancer;

-         Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer);

-         Undiagnosed genital bleeding;

-         Untreated endometrial hyperplasia;

-         Previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary embolism);

-         Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4.)

-         Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction);

-         Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal;

-         Known hypersensitivity to the active substances or to any of the excipients;

-         Porphyria.

 

 

4.4. Special warnings and special precautions for use

 

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

 

Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited.  Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

 

 

Medical examination/follow up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman.

Women should be advised what changes in their breasts should be reported to their doctor or nurse (see ‘Breast cancer’ below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

 

Conditions which need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Femoston, in particular:

 

-         Leiomyoma (uterine fibroids) or endometriosis

-         Risk factors for, thromboembolic disorders (see below)

-         Risk factors for oestrogen dependent tumours, e.g. 1^st degree heredity for breast cancer

-         Hypertension

-         Liver disorders (e.g. liver adenoma)

-         Diabetes mellitus with or without vascular involvement

-         Cholelithiasis

-         Migraine or (severe) headache

-         Systemic lupus erythematosus

-         A history of endometrial hyperplasia (see below)

-         Epilepsy

-         Asthma

-         Otosclerosis

 

Reasons for immediate withdrawal of therapy:

 

Therapy should be discontinued in cases where a contra-indication is discovered and in the following situations:

                        - Jaundice or deterioration in liver function

                        - Significant increase in blood pressure

                        - New onset of migraine-type headache

                        - Pregnancy

 

Endometrial hyperplasia and carcinoma

In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods.  The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8).  After stopping treatment risk may remain elevated for at least 10 years.  

The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.

 

Break-through bleeding and spotting may occur during the first months of treatment.. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

 

Breast cancer

The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.

The randomised placebo-controlled trial, the Womens Health Initiative study (WHI) and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestagen for HRT that becomes apparent after about 3 years (see Section 4.8).

The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.

 

 

HRT, especially oestrogen-progestagen combined treatment, increases the density of

mammographic images which may adversely affect the radiological detection of breast cancer.

 

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8).

Some studies including the WHI trial suggest that the long-term use of combined HRTs may confer a similar, or slightly smaller, risk (see Section 4.8).

 

Venous thromboembolism

-         HRT is associated with a 1.3-3 fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later.

-         Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk.  HRT is therefore contraindicated in these patients (see section 4.3)

-         Generally recognised risk factors for VTE include use of oestrogens, older ages, major surgery, prolonged immobilisation, severe obesity (BMI>30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE.

As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery.  If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended.  Treatment should not be restarted until the woman is completely mobilised.

-         In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening).If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

-         Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk use of HRT.

-          

                        • If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

 

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestagen or oestrogen-only HRT.

Combined oestrogen-progestagen therapy

The relative risk of CAD during use of combined oestrogen+progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen+progestagen use is very low in healthy women close to menopause, but will rise with more advanced age.

Oestrogen-only

Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.

 

Ischaemic stroke

Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8).

 

Other conditions

                        • Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.

                        • Women with pre-existing hypertriglyceridemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

                        • Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex- hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

                         

-           HRT use does not improve cognitive function.  There is some evidence of increased risk of possible dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.

            • Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

            • Women who may be at risk of pregnancy should be advised to adhere to non-hormonal contraceptive methods

 

 

4.5. Interaction with other medicinal products and other forms of Interaction

 

The metabolism of oestrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (eg. phenobarbital, phenytoin, carbamezapin) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.

Herbal preparations containing St John’s wort (Hypericum perforatum) may induce the metabolism of estrogens and progestagens.

Clinically an increased metabolism of estrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.

 

 

4.6. Pregnancy and lactation

 

Pregnancy:

Femoston is not indicated during pregnancy. If pregnancy occurs during medication with Femoston, treatment should be withdrawn immediately.

Data based on a large number of exposed pregnancies indicate no adverse effects of dydrogesterone on the foetus.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of estrogens and progestagens indicate no teratogenic or foetotoxic effect.

 

Lactation:

Femoston is not indicated during lactation.

 

 

4.7. Effects on ability to drive and use machines

 

Femoston does not affect the ability to drive or use machines.

 

 

4.8. Undesirable effects

 

Undesirable effects reported in clinical trials and in postmarketing experience are the following:

 

MedDRA system organ class			Common >1/100, <1/10	Uncommon >1/1,000, <1/100		Rare >1/10,000, <1/1,000	Very rare <1/10,000 incl. isolated reports
Infections and infestations				Cystitis-like syndrome, Vaginal candidiasis
Neoplasms benign, malignant and unspecified				Increase in size of leiomyoma
Blood and the lymphatic system disorders							Haemolytic anaemia
Psychiatric disorders				Depression, Change in libido, Nervousness
Nervous system disorders			Headache, Migraine	Dizziness			Chorea
Eye disorders						Intolerance to contact lenses, Steepening of corneal curvature
Cardiac disorders							Myocardial infarction
Vascular disorders				Hypertension, Peripheral vascular disease, Varicose vein, Venous thromboembolism			Stroke
Gastrointestinal disorders			Nausea, Abdominal pain, Flatulence	Dyspepsia			Vomiting
Hepatobiliary disorders				Gall bladder disease		Alterations in liver function, sometimes with Asthenia or Malaise, Jaundice and Abdominal pain
Skin and subcutaneous tissue disorders					Allergic skin reactions, Rash, Urticaria, Pruritus		Chloasma or melasma, which may persist when drug is discontinued, Erythema multiforme, Erythema nodosum, Vascular purpura, Angioedema
Musculoskeletal and connective tissue disorders			Leg cramps		Back pain
Reproductive system and breast disorders			Breast pain/tenderness, Breakthrough bleeding and spotting, Pelvic pain		Change in cervical erosion, Change in cervical secretion, Dysmenorrhoea, Menorrhagia, Metrorrhagia	Breast enlargement, Premenstrual-like symptoms
Congenital and familial/genetic disorders							Aggravation of porphyria
General disorders and administration site reactions			Asthenia		Peripheral oedema
Investigations	Increase/decrease in weight

 

Other adverse reactions have been reported in association with estrogen/progestagen treatment:

• Probable dementia over the age of 65 (see section 4.4).

 

Breast Cancer risk

 

• An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years.
• Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestagen combinations.
• The level of risk is dependent on the duration of use (see section 4.4).
• Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.

 

Million Women study– Estimated additional risk of breast cancer after 5 years’ use

Age range (years)	Additional cases per 1000 never-users of HRT over a  year period*1	Risk ratio & 95%CI#	Additional cases per 1000 HRT users over 5 years (95%CI)
Oestrogen only HRT
50-65	9-12	1.2	1-2 (0-3)
Combined oestrogen-progestagen
50-65	9-12	1.7	6 (5-7)
#Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

¹ Taken from baseline incidence rates in developed countries

 

US WHI studies - additional risk of breast cancer after 5 years’ use

Age range (years)	Incidence per 1000 women in placebo arm over 5 years	Risk ratio & 95%CI	Additional cases per 1000 HRT users over 5 years (95%CI)
CEE oestrogen-only
50-79	21	0.8 (0.7 – 1.0)	-4 (-6 – 0)*2
CEE+MPA oestrogen & progestagen‡
50-79	14	1.2 (1.0 – 1.5)	+4 (0 – 9)

² WHI study in women with no uterus, which did not show an increase in risk of breast cancer

 

‡When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

 

 

Endometrial cancer

 

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.

In women with an intact uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer increases (see section 4.4). Depending on the duration of oestrogen-only use and oestrogen dose,, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 between the ages of 50 and 65.

Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (R.R of 1 .0 (0.8-1.2)).

 

Ovarian cancer

 

Long-term use of oestrogen-only and combined oestrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer.  In the Million Women Study 5 years of HRT resulted in 1 extra case per 2500 users.

 

Risk of venous thromboembolism

 

HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism.  The occurrence of such an event is more likely in the first year of using HT (see section 4.4.).  Results of the WHI studies are presented:

 

Age range (years)	Incidence per 1000 women in placebo arm over 5 years	Risk ratio and 95%CI	Additional cases per 1000 HRT users
Oral oestrogen-only*3
50-59	7	1.2 (0.6-2.4)	1 (-3 – 10)
Oral combined oestrogen-progestagen
50-59	4	2.3 (1.2 – 4.3)	5 (1 - 13)

³ Study in women with no uterus

 

Risk of coronary artery disease

 

·        The risk of coronary artery disease is slightly increased in users of combined oestrogenprogestagen HRT over the age of 60 (see section 4.4).

 

Risk of ischaemic stroke

 

·        The use of oestrogen-only and oestrogen + progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.

·        This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4.

 

WHI studies combined - Additional risk of ischaemic stroke*⁴ over 5 years’ use

Age range (years)	Incidence per 1000 women in placebo arm over 5 years	Risk ratio and 95%CI	Additional cases per 1000 HRT users
50-59	8	1.3 (1.1-1.6)	3 (1–5)

⁴ No differentiation was made between ischaemic and haemorrhagic stroke

 

4.9. Overdose

 

Both oestradiol and dydrogesterone are substances with low toxicity. Theoretically, symptoms such as nausea, vomiting, sleepiness and dizziness could occur in cases of overdosing. It is unlikely that any specific or symptomatic treatment will be necessary.

Aforementioned information is applicable for overdosing by children also.

 

 

5. PHARMACOLOGICAL PROPERTIES

 

5.1. Pharmacodynamic Properties

 

The ATC code is G03FB08. (Oestrogens: urogenital system and sex hormones)

Sequential hormone replacement therapy (combined oestradiol and dydrogesterone).

 

Oestradiol

The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human oestradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy.

 

Dydrogesterone

Dydrogesterone is an orally-active progestagen.  As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer.  The addition of a progestagen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

 

Clinical trial Information

-         Relief of oestrogen-deficiency symptoms and bleeding patterns.

-         Relief of menopausal symptoms was achieved during the first few weeks of treatment.

-         Regular withdrawal bleeding with Femoston 1/10 occurred in approximately 75-80% of women with a mean duration of 5 days.

 

Withdrawal bleeding usually started on the day of the last pill of the progestagen phase. Break-through bleeding and/or spotting occurred in approximately 10% of the women; amenorrhoea (no bleeding or spotting) occurred in 21-25% of the women for months 10 to 12 of treatment.

 

- With Femoston 2/10, approximately 90% of women had regular withdrawal bleeding. The start day and duration of bleeding, and the number of women with intermittent bleeding was the same as with Femoston 1/10, amenorrhoea occurred in 7-11% of the women for months 10 to 12 of treatments.

                         

• Prevention of osteoporosis

- Oestrogen deficiency at menopause is associated with an increasing boneturnover and decline in bone mass.

- The effect of oestrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

- Evidence from the WHI trial and meta-analysed trials shows that current use of

HRT, alone or in combination with a progestagen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

- After two years of treatment with Femoston 2/10, the increase in lumbar spine bone mineral density (BMD) was 6.7% ± 3.9% (mean ± SD). The percentage of women who maintained or gained BMD in lumbar zone during treatment was 94.5%. For Femoston 1/10 the increase in lumbar spine BMD was 5.2% ± 3.8% (mean ± SD), and the percentage of women with no change or an increase in lumbar spine BMD was 93%.

- Femoston also had an effect on hip BMD. The increase after two years of treatment with 1mg estradiol was 2.7% ± 4.2% (mean ± SD) at femoral neck, 3.5% ± 5.0% (mean ± SD) at trochanter and 2.7%± 6.7% (mean ± SD) at Wards triangle. After two years of treatment with 2mg estradiol these figures were respectively, 2.6% ± 5.0%; 4.6% ± 5.0% and 4.1% ± 7.4%. The percentage of women who maintained or gained BMD in the 3 hip areas after treatment with 1mg estradiol was 67-78% and 71-88% after treatment with 2mg estradiol.

 

 

5.2. Pharmacokinetic Properties

 

Oestradiol

Orally administered oestradiol, comprising particles whose size has been reduced to less than 5 μm, is quickly and efficiently absorbed from the gastrointestinal tract. The primary unconjugated and conjugated metabolites are oestrone and oestrone sulphate. These metabolites can contribute to the oestrogen effect, both directly and after conversion to oestradiol. Oestrogens are excreted in the bile and reabsorbed from the intestine. During this enterohepatic cycle the oestrogens are broken down. Oestrogens are excreted in the urine as biologically inactive glucuronide and sulphate compounds (90 to 95%), or in the faeces (5 to 10%), mostly unconjugated. Oestrogens are excreted in mothers' milk.

During the administration of oral oestradiol to post-menopausal women at 2 mg once a day the C_average is 58 pg/ml, the C_min is 44 pg/ml and the C_max is 93 pg/ml. The E1/E2 (Oestrone/Oestradiol) ratio is 5.8.

 

Dydrogesterone

After oral administration of labelled dydrogesterone, on average 63% of the dose is excreted into the urine. Within 72 hours, excretion is complete.

 

In man, dydrogesterone is completely metabolised. The main metabolite of dydrogesterone is 20α-dihydrodydrogesterone (DHD) and is present in the urine predominantly as the glucoronic acid conjugate. A common feature of all metabolites characterised is the retention of the 4,6 diene-3-one configuration of the parent compound and the absence of 17α-hydroxylation. This explains the absence of oestrogenic and androgenic activity.

 

After oral administration of dydrogesterone, plasma concentrations of DHD are substantially higher as compared to the parent drug. The AUC and C_max ratios of DHD to dydrogesterone are in the order of 40 and 25, respectively. Dydrogesterone is rapidly absorbed. The T_max values of dydrogesterone and DHD vary between 0.5 and 2.5 hours.

 

Mean terminal half lives of dydrogesterone and DHD vary between 5 to 7 and 14 to 17 hours, respectively.

The dihydrodydrogesterone C_average is 13 ng/ml, the C_min is 4.1 ng/ml and the C_max is 63 ng/ml. The dydrogesterone C_average is 0.38 ng/ml the C_min is <0.1 ng/ml and the C_max is 2.5 ng/ml.

Dydrogesterone is not excreted in urine as pregnanediol, like progesterone. Analysis of endogenous progesterone production based on pregnanediol excretion therefore remains possible.

 

 

5.3. Preclinical Safety Data

 

Supraphysiologically high doses (prolonged overdoses) of oestradiol have been associated with the induction of tumours in oestrogen-dependent target organs for all rodent species tested. The changes observed with dydrogesterone in animal toxicity studies are characteristic for progesterone-like compounds. In-vitro and in-vivo data gave no indications of mutagenic effects of dydrogesterone. In long-term studies, doses administered to rats and mice were sufficient to produce hormone-mediated changes, but did not provide tumorogenic potential.

 

6. PHARMACEUTICAL PARTICULARS

                         

                        6.1. List of Excipients

 

Oestradiol only tablets (brick-red):

 

Tablet core:

Lactose

Hypromellose

Maize starch

Colloidal anhydrous silica

Magnesium stearate

 

Film coat:

Hypromellose

Talc

Macrogol 400

Titanium dioxide E171

Iron oxide red E171

Iron oxide black E172

Iron oxides yellow E172

 

Oestradiol/Dydrogesterone tablets (yellow):

 

Tablet core:

Lactose

Hypromellose

Maize starch

Colloidal anhydrous silica

Magnesium stearate

 

Film coat:

Hypromellose

Talc

Macrogol 400

Titanium dioxide (E171)

Iron oxide yellow (E172)

 

 

6.2. Incompatibilities

 

Not applicable.

 

 

6.3. Shelf life

 

3 years.

 

 

6.4. Special precautions for storage

 

Do not store above 30°C.

 

 

6.5. Nature and contents of container

 

The tablets are packed in blister strips of 28. The blister packs are made of PVC/PVdC or PVC film with a covering aluminium foil. Each carton contains 28 or 84 tablets.

 

 

6.6. Instruction for use and handling

 

Not applicable.

 

7. MARKETING AUTHORISATION HOLDER

 

Abbott Healthcare Products Limited

Mansbridge Road

West End

Southampton

SO18 3JD

 

 

8. MARKETING AUTHORISATION NUMBER(S)

 

PL 00512/0113

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

17 January 1995

 

 

10. DATE OF REVISION OF THE TEXT

 

16 January 2012

 

 

Legal category

 

POM

 

Reasons for adding or updating:

• Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC: 19-Apr-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

4.8 Undesirable Effects

Addition of:
 
- Immune System disorders: Systemic Lupus Erythematosus

- Reproductive System and Breast Disorders - addition of Metrorrhagia and postmenopausal spotting (breakthrough bleeding).

- Neoplasms benign, malignant and unspecified:  addition of ovarian and endometrial cancer.

- Nervous System disorders - probable dementia and/or exacerbation of epilepsy

- Vascular disorders - Arterial thromboemolism.

Reasons for adding or updating:

• Change to section 7 - Marketing Authorisation Holder
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 11-Feb-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



 The Abbott Corporation has recently taken over the pharmaceutical business of the Solvay company. As a result the names of the former Solvay affiliate companies are being changed.

 

•           The name of the market authorisation holder will change from Solvay Healthcare Limited to Abbott Healthcare Products Limited - address remains unchanged.

Reasons for adding or updating:

• Change to section 4.1 - Therapeutic Indications
• Change to section 4.2 - Posology and Method of Administration
• Change to section 4.3 - Contra-indications
• Change to section 4.4 - Special Warnings and Precautions for Use
• Change to section 5.1 - Pharmacodynamic Properties
• Change to section 4.8 - Undesirable Effects

Reasons for adding or updating:

• Addition of separate SPCs covering individual presentations