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

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Change to PL number and MAH.  SmPC revision date changed.

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: 02-May-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

PRAC warnings ovarian cancer added and dossier updates.

Reasons for adding or updating:

• Change to section 2 - Qualitative and quantitative composition
• Change to section 4.8 - Undesirable effects
• Change to section 5.2 - Pharmacokinetic properties

Date of revision of text on the SPC: 02-May-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 2..  Editorial change to underline text
Section 4.8  Addition of ADR reporting information
Section 5.2 Change to headings -  'Metabolism changed to Biotransformation'

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: 26-Mar-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



 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 PL00512/0397 to PL 43900/0039
• In section 10 ( Date of revision of text) has been updated to 26/03/2015

Reasons for adding or updating:

• Change to section 2 - Qualitative and quantitative composition
• Change to section 4.3 - Contraindications
• Change to section 4.6 - Fertility, 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

Date of revision of text on the SPC: 18-Mar-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 2:

28 tablets, each containing 0.5 mg 17β-estradiol (as hemihydrate) and 2.5 mg dydrogesterone.

 

Excipient with known effect: lactose monohydrate 117.4 mg

Excipient(s): Lactose

 

For the a full list of excipients, see section 6.1.

Section 4.3:
Moved from the top of the list to the bottom:

•      Known hypersensitivity to the active substances or to any of the excipients listed in section 6.1

Section 4.6:

Pregnancy

Femoston-conti 0.5 mg/2.5 mg is not indicated during pregnancy. If pregnancy occurs during medication with Femoston-conti 0.5 mg/2.5 mg treatment should be withdrawn immediately.

There are no adequate data from the use of estradiol/dydrogesterone in pregnant women. The results of most epidemiological studies to date relevant to inadvertent fetal exposure to combinations of oestrogens and progestogens indicate no teratogenic or foetotoxic effect. There are no adequate data from the use of estradiol/dydrogesterone in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

 

Lactation

Femoston-conti 0.5 mg/2.5 mg is not indicated during lactation.

 

Fertility

Femoston-conti 0.5 mg/2.5 mg is not indicated during fertility.

Section 4.8:

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). *Undesirable effects from spontaneous reporting not observed in clinical trials have been attributed to the frequency “rare”:

Undesirable effects reported in clinical trials and in post marketing experience of all dosage forms are the following:

MedDRA system organ class	Very common ≥1/10	Common ≥1/100 to <1/10	Uncommon ≥1/1,000 to <1/100	Rare ≥1/10,000 to <1/1,000	Very rare <1/10,000
Infections and infestations		Vaginal candidiasis	Cystitis- like  symptoms syndrome, vaginal candidiasis
Neoplasms benign, malignant and unspecified			Increase in size of leiomyoma
Blood and the lymphatic system disorders				Haemolytic anaemia*	Haemolytic anaemia
Immune system disorders			Hypersensitivity		Hypersensitivity
Psychiatric disorders		Depression, nervousness	Depression, Influence on libido nervousness
Nervous system disorders	Headache	Migraine, dizziness headache	Dizziness	Meningioma*	Chorea, meningioma
Eye disorders				Steepening of corneal curvature*, contact lenses intolerance*
Cardiac disorders				Myocardial infarction	Myocardial infarction
Vascular disorders			Venous thromboembolism*, hypertension, peripheral vascular disease, varicose vein	Stroke*	Stroke
Gastrointestinal disorders	Abdominal pain	Nausea, vomiting, abdominal pain, abdominal distension (including flatulence)	Dyspepsia		Vomiting
Hepatobiliary disorders			Abnormal hepatic function occasionally with jaundice asthenia or malaise, and abdominal pain, gall bladder disease disorder	Abnormal hepatic function occasionally with jaundice asthenia or malaise, and abdominal pain.
Skin and subcutaneous tissue disorders		Allergic skin reactions ( e.g. rash, urticaria, pruritus)	Allergic skin reactions ( e.g. rash, urticaria, pruritus)	Angio-edema, vascular purpura, erythema nodosum*, Chloasma or melasma, which may persist when drug is discontinued*	Angioedema, erythema multiforme, erythema nodosum, vascular purpura, chloasma or melasma, which may persist when drug is discontinued.
Musculoskeletal and connective tissue disorders	Back pain	Leg cramps	Back pain	Leg cramps*
Reproductive system and breast disorders	Breast pain/tenderness	Menstrual disorders (including postmenopausal spotting, metrorrha-gia, menorrhagia, oligo-/ amenorrhoea, irregular menstruation, dysmenor-rhoea), pelvic pain, cervical discharge Breast pain/tenderness, metrorrhagia and postmenopausal spotting, pelvic pain	Breast enlargement, premenstrual syndrome Uterine cervical erosion, cervical discharge, dysmenorrhoea, menorrhagia	Breast enlargement, premenstrual syndrome
Congenital and familial/genetic disorders					Aggravated porphyria
General disorders and administration site reactions		Asthenic conditions (asthenia, fatigue, malaise), peripheral oedema Asthenia	Peripheral oedema
Investigations		Increased weight decreased weight	Decreased weight

* see below for further information

...

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 meningioma).

 

Immune system disorders:

Systemic lupus erythematosus

 

Metabolism and nutrition disorders:

Hypertriglyceridemia

 

Nervous system disorders:

Probable dementia, chorea, exacerbation of epilepsy

 

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

 

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

Renal and urinary disorders:

 Urinary incontinence

Section 4.9:

No case of overdose has been reported for Femoston-conti 0.5 mg/2.5 mg.

 

Both estradiol and dydrogesterone are substances with low toxicity. Theoretically, Symptoms such as nausea, vomiting, breast tenderness, somnolence and 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.

 

Aforementioned information is also applicable for overdosing in children.

Section 5.1:

....

Clinical trial information

• Relief of oestrogen-deficiency symptoms and bleeding patterns

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

With Femoston-conti 0.5 mg/2.5 mg the reduction of moderate to severe hot flushes was statistically significant versus placebo from week 4 onward. The number of moderate to severe hot flushes decreased further until end of treatment period in week 13.
 In two studies amenorrhoea (no bleeding or spotting) was seen in 91% and in 88% of the women respectively during months 10-12 of treatment. Irregular bleeding and or spotting appeared in 10% and 21% of the women during the first 3 months of treatment and in 9% and in 12% during months 10-12 of treatment.

 

Relief of climacteric complaints was achieved during the first weeks of treatment.

Section 5.2:

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 single dose pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for each dose of micronized estradiol. Data is presented as mean (SD).

 

Estradiol 0.5 mg
Parameters	E2	E1	Parameters	E1S
Cmax (pg/mL)	34.8 (30.4)	182 (110)	Cmax (ng/mL)	6.98 (3.32)
Cmin (pg/mL)	-	-	-	-
Cav (pg/mL)	21.5 (16.0)	-	-	-
AUC0-t (pg.h/mL)	516 (383)	2959 (2135)	AUC0-t (ng.h/mL)	82.0 (42.6)

 

Estradiol 0.5mg

	E2 (estradiol)	E1 (estrone)		E1S (estrone sulphate)
Cmax (pg/ml)	20.6	121	Cmax (ng/ml)	6.53
AUCt (pg*h/ml)	601	3505	AUCt (pg*h/ml)	116

 

• 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).

Estrogens are found either unbound or weakly associated to serum albumin by nonspecific binding or specifically bound with high affinity to sex hormone-binding globulin (SHBG). The percentage of SHBG binding varies between 9 and 37% in premenopausal and 23-53% in postmenopausal women receiving conjugated estrogens.

...

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 provides the mean steady state single dose pharmacokinetic parameters of dydrogesterone (D) and dihydrodydrogesterone (DHD). Data is presented as mean (SD).

 

 Dydrogesterone 2.5 mg

 

		D		DHD
Cmax (ng/ml)		0.6		17.5
AUCinf (ng*h/ml)		2.84		91.7
	Dydrogesterone 2.5 mg
	Parameters		D			DHD
	Cmax (ng/mL)		0.759 (0.313)			18.9 (7.22)
	Cmin (ng/mL)		0.0309 (0.0209)			-
	Cav (ng/mL)		0.117 (0.0455)			-
	AUC0-t (ng.h/mL)		2.81 (1.09)			90.4 (44.1)

...

Section 5.3:

There are no preclinical safety data which could be 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).

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: 17-Jul-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

* In section 7 (Marketing Authorisation Holder), MAH has a new site address
* In section 10 (Date of revsion of the text), updated to reflect the implemaentation date of new site

Reasons for adding or updating:

• New SPC for eMC ie an SPC for an existing product, but one that is new for the eMC

Legal Category:POM

Black Triangle (CHM): NO