REC20788+REC30040_BP23002

Note:

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2. What you need to know before you take Yasminelle

Warnings and precautions

[….]

·        If you experience symptoms of angioedema such as swollen face, tongue and/or throat and/or difficulty swallowing or hives potentially with difficulty breathing contact a doctor immediately. Products containing oestrogens may cause or worsen the symptoms of hereditary and acquired angioedema.

·        if you have hereditary angioedema, products containing oestrogens may cause or worsen symptoms. You should see your doctor immediately if you experience symptoms of angioedema such as swollen face, tongue and/or throat and/or difficulty swallowing or hives together with difficulty breathing.

4.                  Possible side effects

[….]

Serious side effects

Contact a doctor immediately if you experience any of the following symptoms of angioedema: swollen face, tongue and/or throat and/or difficulty swallowing or hives potentially with difficulty breathing (see also section “Warnings and precautions”).

Uncommon side effects (between 1 and 10 in every 1,000 users may be affected):

[….]

-         sudden swelling of the skin and/or mucous membranes (e.g. tongue or throat), and/or difficulty swallowing or hives together with difficulty breathing (angioedema), hair loss (alopecia), eczema, itching, rashes, dry skin, oily skin disorders (seborrheic dermatitis)

6.                  Contents of the pack and other information

What Yasminelle contains

see section 2 “Yasminelle contains lactose”.

[….]

This medicine medicinal product is authorised in the Member States of the EEA European Economic Area under the following names:

[….]

This leaflet was last revised in November 2022 May 2023.

REC20788+REC30040_BP23002

Note:

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Text in blue = added text

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4.4 Special warnings and precautions for use

·        Other conditions

In women with hereditary angioedema eExogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

4.8 Undesirable effects

[In the Adverse drug reactions table,]:

-         Exacerbation of symptoms of hereditary and acquired angioedema [has been added to the “Not known” column under “Immune system disorders”.] 

-         Angioedema [has been deleted from the  “uncommon” column under “Skin and subcutaneous disorders”.] 

Description of selected adverse reactions

The following serious adverse events have been reported in women using COCs, which are discussed in section 4.4 Special warning and precautions for use:

-                In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.

10. Date of revision of the text

November 2022 May 2023

REC30965, BP22056

Note:

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Text in red with strikethrough = deleted text

4.3 Contraindications

[….]

Yasminelle is contraindicated for concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see sections 4.4 and 4.5).

4.4 Special warnings and precautions for use

[….]

ALT elevations

During clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequent in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs). Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs (see sections 4.3 and 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

During clinical trials with patients treated for hepatitis C virus infections (HCV) with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequent in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs). Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs (see sections 4.3).

Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, or glecaprevir/pibrentasvir may increase the risk of ALT elevations (see sections 4.3 and 4.4).

Therefore, Yasminelle-users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with thisthese combination drug regimens. Yasminelle can be restarted 2 weeks following completion of treatment with thisthese combination drug regimens.

10 Date of revision of the text

September 2022 November 2022

REC30965, BP22056

Note:

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Text in blue = added text

Text in red with strikethrough = deleted text

2. What you need to know before you take Yasminelle

[….]

Do not use Yasminelle if you have hepatitis C and are taking the medicinal products containing ombitasvir/paritaprevir/ritonavir, and dasabuvir, or glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see also in section “Other medicines and Yasminelle”).

[….]

Other medicines and Yasminelle

Do not use Yasminelle if you have hepatitis C and are taking the medicinal products containing ombitasvir/paritaprevir/ritonavir, and dasabuvir, or glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, as thisthese products may cause increases in liver function blood test results (increase in ALT liver enzyme).

[….]

6. Contents of the pack and other information

[….]

This leaflet was last revised in September 2022 November 2022.

BP22036, REC30610

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

6. Contents of the pack and other information

[….]

Marketing Authorisation Holder

Bayer Limited, 1st Floor, The Grange Offices, The Grange, Brewery Road, Stillorgan, Co. Dublin, A94 H2K7, Ireland

The Atrium,

Blackthorn road,

Dublin 18,

Ireland

[….]

This leaflet was last revised in November 2021September 2022.

[….]

BP22036, REC30610

Note:

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7. Marketing Authorisation holder

Bayer Limited

1st Floor

The Grange Offices

The Grange

Brewery Road

Stillorgan

Co. Dublin

A94 H2K7

The Atrium

Blackthorn road

Dublin 18

Ireland

10. Date of revision of text

November 2021 September 2022

PIL

[BP21028_BEC19714+19965]

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

2. What you need to know before you take Yasminelle

Do not use Yasminelle:

[…]

Do not use Yasminelle if you have hepatitis C and are taking the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir or glecaprevir/pibrentasvir (see also in section “Other medicines and Yasminelle”).

[…]

Other medicines and Yasminelle

[…]

Do not use Yasminelle if you have hepatitis C and are taking the medicinal products containing

ombitasvir/paritaprevir/ritonavir and dasabuvir or glecaprevir/pibrentasvir as this may cause

increases in liver function blood test results (increase in ALT liver enzyme).

[…]

[…]

6. Contents of the pack and other information                                                                                          

[…]

What Yasminelle looks like and content of the pack

[…]

• Yasminelle tablets are film-coated tablets; the core of the tablet is coated. The tablets are light pink, round with convex surfaces, one side is markedembossed with the letters "DS" in a regular hexagon.

[…]

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

• Austria, Belgium, Cyprus, Czech Republic, Estonia, Finland, Germany, Greece, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Norway, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden: Yasminelle

[…]

This leaflet was last revised in  November 2021August 2020.

Summary of Product Characteristics

[BP21028_BEC19714+19965]

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

3. PHARMACEUTICAL FORM

Film-coated tablets

Light pink, round tablets with convex faces, one side markedembossed with the letters "DS" in a regular hexagon.

[…]

4.3 Contraindications

[…]

Yasminelle is contraindicated for concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir or medicinal products containing glecaprevir/pibrentasvir (see sections 4.4 and 4.5).

[…]

4.4 Special warnings and precautions for use

[…]

ALT elevations

During clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequent in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs). Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs (see sections 4.3 and 4.5).

[…]

4.5 Interaction with other medicinal products and other forms of interaction

[…]

• Pharmacodynamic interactions

Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, or glecaprevir/pibrentasvir may increase the risk of ALT elevations (see sections 4.3 and 4.4).

[…]

10. DATE OF REVISION OF THE TEXT

November 2021August 2020

(BP20078 BEC18063)

5.3 Preclinical safety data

[…]

Environmental Risk Assessment (ERA)

Environmental risk assessment studies have shown that ethinylestradiol and drospirenone have the potential of posing a risk to the aquatic environment (see section 6.6).

[…]

6.6 Special precautions for disposal

This medicinal product may pose a risk to the environment (see section 5.3).

[…]

10. DATE OF REVISION OF THE TEXT

August 2020July 2021

Editorial update: "Ireland" has been added the the Marketing Authorisation Holder address in section 7.

Editorial update: "Ireland" has been added the the Marketing Authorisation Holder address in section 6.

Reason for change:

• Addition of lactose monohydrate value in section 2 of the SmPC
• Additional information on special populations included in section 4.2.
• Contact details for reporting of side effects updated for Ireland.
• Editorial updates included.

Section 2: QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 0.020 mg ethinylestradiol (as betadex clathrate) and 3 mg drospirenone.

Excipient with known effect: lactose 46 mg (as lactose monohydrate 48.18 mg)

[….]

Section 4.2: Posology and method of administration

[….]

Additional information on special populations

Paediatric population

Yasminelle is only indicated after menarche.

Elderly

Yasminelle is not indicated after menopause.

Patients with hepatic impairment

Yasminelle is contraindicated in women with severe hepatic diseases. See also sections 4.3 and 5.2.

Patients with renal impairment

Yasminelle is contraindicated in women with severe renal insufficiency or acute renal failure. See also sections 4.3 and 5.2.

Section 4.4 Special warnings and precautions for use

[….]

• Other conditions

[….]

Worsening of endogenous depression epilepsy, of Crohn’s disease and of ulcerative colitis has been reported during COC use.

[….]

Section 4.8: Undesirable effects

Reporting of suspected adverse reactions

[….]

Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL, Dublin 2; Tel +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Section 10: DATE OF REVISION OF THE TEXT

August 2020 December 2018

Reason for change:

• Additional information on special populations included in section 2.
• Contact details for reporting of side effects updated for Ireland.
• Editorial updates included

Section: What is in this leaflet

[….]

Psychiatric disorders

 [….]

Section 1: What Yasminelle is and what it is used for

[….]

• Each film-coated tablet contains a small amount of two different female hormones, namely drospirenone and ethinylestradiol.

[….]

Section 2: What you need to know before you take Yasminelle

[….]

Additional information on special populations

Children and adolescents
Yasminelle is not intended for use in females whose periods have not yet started.

Older women
Yasminelle is not intended for use after the menopause.

Women with liver impairment
Do not take Yasminelle if you suffer from liver disease. See also sections ‘Do not take Yasminelle’ and ‘Warnings and precautions’.

Women with kidney impairment
Do not take Yasminelle if you are suffering from poorly functioning kidneys or acute kidney failure. See also sections ‘Do not use Yasminelle’ and ‘Warnings and precautions’.

Section 3: How to take Yasminelle

[….]

The strip contains 21 film-coated tablets.

[….]

Section 4 Reporting of side effects

[….]

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

[….]

Section 6: Contents of the pack and other information

[….]

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

• Austria, Belgium, Cyprus, Czech Republic, Denmark, Estonia, Finland, Germany, Greece, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Norway, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden: Yasminelle

 [….]

This leaflet was last revised in August 2020.December 2018.

The text below in red has been added.

4.3 Contraindications

[…]

Yasminelle is contraindicated for concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir (see sections 4.4 and 4.5).

4.4 Special warnings and precautions for use

 […]

ALT elevations

During clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequent in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

[…]

·        Pharmacodynamic interactions

Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see sections 4.3 and 4.4).

Therefore, Yasminelle-users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen. Yasminelle can be restarted 2 weeks following completion of treatment with this combination drug regimen.

4.9 Overdose

There has not yet been any experience of overdose with Yasminelle. On the basis of general experience with combined oral contraceptives, symptoms that may possibly occur in this case are nausea, vomiting and withdrawal bleeding. Withdrawal bleeding may even occur in girls before their menarche, if they accidentally take the medicinal product. There are no antidotes and further treatment should be symptomatic.

[Deleted text; new text]

Section 4.3:

………………

·         Hypersensitivity to the active substances or to any of the excipients of listed in section 6.1.

………………

Section 4.5:

………………

Substances with variable effects on the clearance of COCs:

When co-administered with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of estrogen or progestins. The net effect of these changes may be clinically relevant in some cases.

Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.

The main metabolites of drospirenone in human plasma are generated without involvement of the cytochrome P450 system. Inhibitors of this enzyme system are therefore unlikely to influence the metabolism of drospirenone.

Substances decreasing the clearance of COCs (enzyme inhibitors):

The clinical relevance of potential interactions with enzyme inhibitors remains unknown.

Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of the estrogen or the progestin or both.

In a multiple dose study with a drospirenone (3 mg/day) / ethinylestradiol (0.02 mg/day) combination, co-administration of the strong CYP3A4 inhibitor ketoconazole for 10 days increased the AUC(0-24h) of drospirenone and ethinylestradiol 2.7-fold and 1.4-fold, respectively.

Etoricoxib doses of 60 to 120 mg/day have been shown to increase plasma concentrations of ethinylestradiol 1.4 to 1.6-fold, respectively when taken concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

·         Effects of Yasminelle on other medicinal products

Oral contraceptives COCs may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).

Based on in vitro inhibition studies and in vivo interaction studies in female volunteers using omeprazole, simvastatin andor midazolam as marker substrate, an a clinically relevant interaction of drospirenone at doses of 3 mg with the cytochrome P450 mediated metabolism of other active substances is unlikely.

Clinical data suggests that ethinylestradiol is inhibiting the clearance of CYP1A2 substrates leading to a weak (e.g. theophylline) or moderate (e.g. tizanidine) increase in their plasma concentration.  

………………

Section 4.8:

………………

………………

The following serious adverse events have been reported in women using COCs, which are discussed in section 4.4 Special warnings and precautions for use:

………………

Section 5.2:

·         Drospirenone

………………

Biotransformation

Drospirenone is extensively metabolized after oral administration. The major metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, both of which are formed without involvement of the P450 system. Drospirenone is metabolized to a minor extent by cytochrome P450 3A4 and has demonstrated a capacity to inhibit this enzyme and cytochrome P450 1A1, cytochrome P450 2C9 and cytochrome P450 2C19 in vitro., formed by reduction and subsequent sulfatation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4.

In vitro, drospirenone is capable to inhibit weakly to moderately the cytochrome P450 enzymes CYP1A1, CYP2C9, CYP2C19 and CYP3A4.

………………

·         Ethinylestradiol

………………

Biotransformation

Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. significant gut and hepatic first-pass metabolism. Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The metabolic clearance rate of ethinylestradiol is about 5 ml/min/kg.

In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism based inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

………………

Section 10:

Date of revision of the text updated from ‘January 2015’ to ‘August 2015’

9.                DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:     24th July 2006

Date of the last renewal:        4th August 20102015

10.            DATE OF REVISION OF THE TEXT

January 2015March 2015

2.                QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 0.020 mg ethinylestradiol (as betadex clathrate) and 3 mg drospirenone.

Excipient with known effect: lactose 46 mg

For thea full list of excipients, see section 6.1.

3.                PHARMACEUTICAL FORM

Film-coated tablets

Light pink, round tablets with convex faces, one side embossed with the letters "DS" in a regular hexagon.

4.                CLINICAL PARTICULARS

4.2            Posology and method of administration

MethodRoute of administration: oral use

Posology

Dosage regimen

4.3            …Contraindications

…

·       Hypersensitivity to the active substances or to any of the excipients of listed in section 6.1.Yasminelle film-coated tablets

4.5            Interaction with other medicinal products and other forms of interaction

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

·         EffectsInfluence of other medicinal products on Yasminelle

Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and whichbetween oral contraceptives and other medicinal products may lead to breakthrough bleeding and/or contraceptive failure.

Management

Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.

Short-term treatment

Women on treatment with enzyme-inducing drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method must be used during the whole time of the concomitant drug therapy and for 28 days after its discontinuation. If the drug therapy runs beyond the end of the tablets in the COC pack, the next COC pack should be started right after the previous one without the usual tablet-free interval.

Long-term treatment

In women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal, method of contraception is recommended.

The following interactions have been reported in the literature.

Substnces increasing the clearance of COCs (diminished efficacy of COCs by enzyme induction), e.g.:Hepatic metabolism

Interactions can occur with drugs that induce hepatic enzymes which can result in increased clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, bosentan and HIV-medication (e.g. ritonavir, nevirapine) and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing the herbal remedy St. John's Wort (hypericum perforatum)). Maximal enzyme induction is generally seen in about 10 days but may then be sustained for at least 4 weeks after the cessation of drug therapy.

Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, and HIV medication ritonavir, nevirapine and efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John's Wort (hypericum perforatum).

Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure (see Management).

Substances with variable effects on the clearance of COCs:Interference with Enterohepatic Circulation

When co-administered with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentration of estrogen or progestins. The net effect of these changes may be clinically relevant in some cases.

Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.

Contraceptive failures have also been reported with antibiotics, such as penicillins and tetracyclines. The mechanism of this effect has not been elucidated.

Management

Women on short-term treatment with any of the above-mentioned classes of medicinal products or individual active substances (hepatic enzyme-inducing medicine) besides rifampicin should temporarily use a barrier method in addition to the COC, i.e. during the time of concomitant medicinal product administration and for 7 days after their discontinuation.

For women on rifampicin a barrier method should be used in addition to the COC during the time of rifampicin administration and for 28 days after its discontinuation.

In women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal, method of contraception is recommended.

Women on treatment with antibiotics (besides rifampicin, see above) should use the barrier method until 7 days after discontinuation.

If concomitant medicinal product administration runs beyond the end of the tablets in the COC blister pack, the next COC pack should be started without the usual tablet-free interval.

The main metabolites of drospirenone in human plasma are generated without involvement of the cytochrome P450 system. Inhibitors of this enzyme system are therefore unlikely to influence the metabolism of drospirenone.

·                 EffectsInfluence of Yasminelle on other medicinal products

Oral contraceptives may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).

Based on in vitro inhibition studies and in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrate, an interaction of drospirenone at doses of 3 mg with the metabolism of other active substances is unlikely.

·         Other forms of interactions

In patients without renal insufficiency, the concomitant use of drospirenone and ACE-inhibitors or NSAIDs did not show a significant effect on serum potassium. Nevertheless, concomitant use of Yasminelle with aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, serum potassium should be tested during the first treatment cycle. See also section 4.4.

·         Laboratory tests

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid-binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity.

4.6            Fertility, pPregnancy and lactation

Pregnancy

Yasminelle is not indicated during pregnancy.

If pregnancy occurs during use of Yasminelle, the preparation should be withdrawn immediately. Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during pregnancy.

Animal studies have shown undesirable effects during pregnancy and lactation (see section 5.3). Based on these animal data, undesirable effects due to hormonal action of the active compounds cannot be excluded. However, general experience with COCs during pregnancy did not provide evidence for an actual undesirable effect in humans.

The available data regarding the use of Yasminelle during pregnancy are too limited to permit conclusions concerning negative effects of Yasminelle on pregnancy, health of the foetus or neonate. To date, no relevant epidemiological data are available.

The increased risk of VTE during the postpartum period should be considered when re-starting Yasminelle (see section 4.2 and 4.4).

Breastfeeding

Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should generally not be recommended until the breast-feeding mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk during COC use. These amounts may affect the child.

4.8            Undesirable effects

For serious undesirable effects in COC users see also section 4.4.

The following adverse drug reactions have been reported during use of Yasminelle:

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Description of selected adverse reactions

An increased risk of arterial and venous thrombotic and thrombo-embolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4.

For venous thromboembolic events (deep vein thrombosis, pulmonary embolism) and arterial thromboembolic events (myocardial infarction, cerebrovascular accident), breast cancer, focal nodular hyperplasia (benign liver tumors) and migraine see also sections 4.3 and 4.4.Description of selected adverse reactions

Adverse reactions with very low frequency or with delayed onset of symptoms which are considered to be related to the group of combined oral contraceptives are listed below (see also sections 4.3 and 4.4:

Tumours

·       The frequency of diagnosis of breast cancer is very slightly increased among OC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with COC use is unknown.

·       Liver tumors (benign and malignant)

Other conditions

·       Erythema nodosum, erythema multiforme

·       Women with hypertriglyceridemia (increased risk of pancreatitis when using COCs)

·       Hypertension

·       Occurrence or deterioration of conditions for which association with COC use is not conclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss

·       In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema

·       Liver function disturbances

·       Changes in glucose tolerance or effect on peripheral insulin resistance

·       Crohn’s disease, ulcerative colitis.

·       Chloasma

·       Hypersensitivity (including symptoms such as rash, urticaria)

The following serious adverse events have been reported in women using COCs, which are discussed in section 4.4 Special warning and precautions for use:

-         Venous thromboembolic disorders;

-         Arterial thromboembolic disorders;

-         Hypertension;

-         Liver tumours;

-         Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn’s disease, ulcerative colitis, epilepsy, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uremic syndrome, cholestatic jaundice;

-         Chloasma;

-         Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal.

-         In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.

The frequency of diagnosis of breast cancer is very slightly increased among COC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with COC use is unknown. For further information, see sections 4.3 and 4.4

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with oral contraceptives (see section 4.5).

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

5.                PHARMACOLOGICAL PROPERTIES

5.2            Pharmacokinetic properties

·       Drospirenone

…

BiotransformationMetabolism

Drospirenone is extensively metabolized after oral administration. The major metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, both of which are formed without involvement of the P450 system. Drospirenone is metabolized to a minor extent by cytochrome P450 3A4 and has demonstrated a capacity to inhibit this enzyme and cytochrome P450 1A1, cytochrome P450 2C9 and cytochrome P450 2C19 in vitro.

…

·       Ethinylestradiol

…

BiotransformationMetabolism

Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The metabolic clearance rate of ethinyl­estradiol is about 5 ml/min/kg.

…

6.                PHARMACEUTICAL PARTICULARS

6.6            Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.No special requirements.

10.            DATE OF REVISION OF THE TEXT

September 2014January 2015

4.     CLINICAL PARTICULARS

4.1  Therapeutic indications

Oral contraception.

The decision to prescribe Yasminelle should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Yasminelle compares with other combined hormonal contraceptives (CHCs), see sections 4.3 and 4.4.

4.3  Contraindications

Combined hormonal contraceptives (CHOCs) should not be used in the followingpresence of any of the conditions listed below. Should any of the conditions appear for the first time during CHOC use, the product should be stopped immediately.

·       Presence or risk of venous thromboembolism (VTE)

o   Venous thromboembolism – current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE]).

o   Known hereditary or acquired predisposition for venous thromboembolism, such as APC resistance, (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency

o   Major surgery with prolonged immobilisation (see section 4.4)

o   A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4)

·       Presence or risk of arterial thromboembolism (ATE)

o   Arterial thromboembolism – current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)

o   Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA)

o   Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).

o   History of migraine with focal neurological symptoms.

o   A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) or to the presence of one serious risk factor such as:

·       diabetes mellitus with vascular symptoms

·       severe hypertension

·       severe dyslipoproteinaemia

·       Venous thrombosis present or in history (deep venous thrombosis, pulmonary embolism)

·       Arterial  thrombosis present or in history (e.g. myocardial infarction) or prodromal conditions (e.g. angina pectoris and transient ischaemic attack)

·       Cerebrovascular accident present or in history

·       The presence of a severe or multiple risk factor(s) for arterial thrombosis:

·       diabetes mellitus with vascular symptoms

·       severe hypertension

·       severe dyslipoproteinemia

·       Hereditary or acquired predisposition for venous or arterial thrombosis, such as APC-resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant)

·       Presence or history of severe hepatic disease as long as liver function values have not returned to normal

·       Severe renal insufficiency or acute renal failure

·       Presence or history of liver tumours (benign or malignant)

·       Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts)

·       Undiagnosed vaginal bleeding

·       History of migraine with focal neurological symptoms

·       Hypersensitivity to the active substances or to any of the excipients of Yasminelle film-coated tablets

4.4  Special warnings and precautions for use

Warnings

·       If any of the conditions or risk factors mentioned below is present, the suitability of Yasminelle should be discussed with the woman.

·       In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of Yasminelle should be discontinued.

·       In case of suspected or confirmed VTE or ATE, CHC use should be discontinued. In case anti-coagulant therapy is started, adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).

If any of the conditions/risk factors mentioned below is present, the benefits of COC use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether COC use should be discontinued.

·       Circulatory Disorders

Risk of venous thromboembolism (VTE)

The use of any combined hormonal contraceptive (CHOC) carries an increaseds the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel , norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as Yasminelle may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with Yasminelle, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.

In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below).

The excess risk of VTE is highest during the first year a woman initially starts using a COC or when she restarts COC use after a pill-free interval of at least a month. It is estimated^[1] that out of 10,000 women who use a CHC containing drospirenone between 9 and 12 women will develop a VTE in one year; this compares with about 6[2]  in women who use a levonorgestrel-containing CHC.

In both cases, the number of VTEs per year is fewer than the number expected during pregnancy or in the postpartum period. Epidemiological studies have shown that the incidence of VTE in women with no known risk factors for VTE who use low dose oestrogen (<50 µg ethinylestradiol combined oral contraceptives) ranges from about 20 cases per 100,000 woman-years (for levonorgestrel-containing COCs ) to 40 cases per 100,000 women-years (for desogestrel/ gestodene-containing COCs). This compares with 5 to 10 cases per 100,000 woman-years for non-users and 60 cases per 100,000 pregnancies. VTE may beis fatal in 1-2% of the cases.

Number of VTE events per 10,000 women in one year

Epidemiological studies have shown that the risk of VTE for drospirenone-containing COCs is higher than for levonorgestrel-containing COCs (so-called second generation preparations) and may be similar to the risk for desogestrel/ gestodene-containing COCs (so-called third generation preparations).

Epidemiological studies have also associated the use of combined COCs with an increased risk for arterial (myocardial infarction, transient ischaemic attack) thromboembolism.

Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries., in contraceptive pill users. There is no consensus as to whether the occurrence of these events is associated with the use of hormonal contraceptives.

Risk factors for VTE

The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).

Yasminelle is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).

Table: Risk factors for VTE

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.

The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the puerperium, must be considered (for information on “Pregnancy and lactation” see section 4.6).

Symptoms of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident can include:

·       unusual unilateral leg pain and/ or swelling

·       sudden severe pain in the chest, whether or not it radiates to the left arm

·       sudden breathlessness

·       sudden onset of coughing

·       any unusual, severe, prolonged headache

·       sudden partial or complete loss of vision

·       diplopia

·       slurred speech or aphasia

·       vertigo

·       collapse with or without focal seizure

·       weakness or very marked numbness suddenly affecting one side or one part of the body

·       motor disturbances

·       ‘acute’ abdomen.

The risk for venous thromboembolic complications in COCs users increases with:

·       increasing age

·       a positive family history (venous thromboembolism ever in a sibling or parent at relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any COC use.

·       prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Antithrombotic treatment should be considered if the pills have not been discontinued in advance.

·       obesity (body mass index over 30 kg/m²).

·       there is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.

The risk of arterial thrombo-embolic complications or of a cerebrovascular accident in COC users increases with:

·       increasing age

·       smoking (women over 35 years should be strongly advised not to smoke if they wish to use an COC)

·       dyslipoproteinemia

·       hypertension

·       migraine

·       obesity (body mass index over 30 kg/m²)

·       a positive family history (arterial thromboembolism ever in a sibling or parent at relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any COC use

·       valvular heart disease

·       atrial fibrillation

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of deep vein thrombosis (DVT) can include:

- unilateral swelling of the leg and/or foot or along a vein in the leg;

- pain or tenderness in the leg which may be felt only when standing or walking,

- increased warmth in the affected leg; red or discoloured skin on the leg.

Symptoms of pulmonary embolism (PE) can include:

- sudden onset of unexplained shortness of breath or rapid breathing;

- sudden coughing which may be associated with haemoptysis;

- sharp chest pain;

- severe light headedness or dizziness;

- rapid or irregular heartbeat.

Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).

Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.

If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.

Risk of arterial thromboembolism (ATE)

Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.

Risk factors for ATE

The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Yasminelle is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).

Table: Risk factors for ATE

Symptoms of ATE

In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of a cerebrovascular accident can include:

- sudden numbness or weakness of the face, arm or leg, especially on one side of the body;

- sudden trouble walking, dizziness, loss of balance or coordination;

- sudden confusion, trouble speaking or understanding;

- sudden trouble seeing in one or both eyes;

- sudden, severe or prolonged headache with no known cause;

- loss of consciousness or fainting with or without seizure.

Temporary symptoms suggest the event is a transient ischaemic attack (TIA).

Symptoms of myocardial infarction (MI) can include:

- pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;

- discomfort radiating to the back, jaw, throat, arm, stomach;

- feeling of being full, having indigestion or choking;

- sweating, nausea, vomiting or dizziness;

- extreme weakness, anxiety, or shortness of breath;

- rapid or irregular heartbeats.

The presence of one serious risk factor or multiple risk factors for venous or arterial disease, respectively, can also constitute a contra-indication. The possibility of anticoagulant therapy should also be taken into account. COC users should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, COC use should be discontinued. Adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).

The increased risk of thromboembolism in the puerperium must be considered (for information on "Pregnancy and Lactation" see section 4.6).

Other medical conditions which have been associated with adverse vascular events include diabetes mellitus, systemic lupus erythematosus, haemolytic uremic syndrome and chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease.

An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

Medical examination/consultation

Prior to the initiation or reinstitution of Yasminelle a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contra-indications (see section 4.3) and warnings (see section 4.4). It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of Yasminelle compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis.

The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.

Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

4.6 Pregnancy and lactation

The increased risk of VTE during the postpartum period should be considered when re-starting Yasminelle (see section 4.2 and 4.4).

4.8 Undesirable effects

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Description of selected adverse reactions

An increased risk of arterial and venous thrombotic and thrombo-embolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4.

…

The frequency of diagnosis of breast cancer is very slightly increased among COC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with COC use is unknown. For further information, see sections 4.3 and 4.4.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

10.  DATE OF REVISION OF THE TEXT

September 2014

• Pancreatitis or a history thereof if associated with severe hypertriglyceridemia

Change of date of revision of text (Section 10):

April 2013

Section 4.8: Undesirable effects

 .............................

 ....................................

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

The following serious adverse events have been reported in women using COCs, which are discussed in section 4.4 Special warning and precautions for use:

-          Venous thromboembolic disorders;

-          Arterial thromboembolic disorders;

-          Hypertension;

-          Liver tumours;

-          Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn’s disease, ulcerative colitis, epilepsy, migraine, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uremic syndrome, cholestatic jaundice;

 ...............................

Section 10: Date of Revision of the text

Main Changes to the SPC

Section 4.2 Posology and method of administration

Updated information provided regarding advice in case of gastro-intestinal disturbances.

Section 4.4 Special warnings and precautions for use

Addition of the following information regarding the risk of circulatory disorders (arterial thrombo-embolic complications or cerebrovascular accident) in COC users:

Risk increases with

·   obesity (body mass index over 30 kg/m²).

·   a positive family history (arterial thromboembolism ever in a sibling or parent at relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any COC use.

Updated information regarding the possible increased risk of cervical cancer in long-term users of COCs (> 5 years).

Updated information provided regarding monitoring of serum potassium in patients presenting with renal insufficiency during the first treatment cycle.

Section 4.5 Interaction with other medicinal products and other forms of interaction

Updated information provided regarding women on chronic treatment with hepatic enzyme-inducing active substances.

Section 5.2 Pharmacokinetic properties

Updated information regarding the effect of drospirenone on special populations (hepatic impairment).