REC20788+REC30040_BP23003

Note:

Text in black = unchanged text

Text in blue = added text

Text in red with strikethrough = deleted text

2. What you need to know before you take Yasmin

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 the 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”).

5. How to store Yasmin

Do not store above 30 °C. Store in the original packaging blister in order to protect from moisture.

6. Contents of the pack and other information

What Yasmin contains

See section 2 “Yasmin 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 November 2023.

REC20788+REC30040_BP23003

Note:

Text in black = unchanged text

Text in blue = added text

Text in red with strikethrough = deleted text

2. What you need to know before you take Yasmin

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 the 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”).

5. How to store Yasmin

Do not store above 30 °C. Store in the original packaging blister in order to protect from moisture.

6. Contents of the pack and other information

What Yasmin contains

See section 2 “Yasmin 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 November 2023.

REC20788+REC30040_BP23003

Note:

Text in black = unchanged text

Text in blue = added text

Text in red with strikethrough = deleted text

2. What you need to know before you take Yasmin

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 the 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”).

5. How to store Yasmin

Do not store above 30 °C. Store in the original packaging blister in order to protect from moisture.

6. Contents of the pack and other information

What Yasmin contains

See section 2 “Yasmin 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 November 2023.

REC20788+REC30040_BP23003

Note:

Text in black = unchanged text

Text in blue = added text

Text in red with strikethrough = deleted text

2. What you need to know before you take Yasmin

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 the 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”).

5. How to store Yasmin

Do not store above 30 °C. Store in the original packaging blister in order to protect from moisture.

6. Contents of the pack and other information

What Yasmin contains

See section 2 “Yasmin 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 November 2023.

REC20788+REC30040_BP23003

Note:

Text in black = unchanged text

Text in blue = added text

Text in red with strikethrough = deleted text

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”.] 

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 warnings and precautions for use:

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

6.4 Special precautions for storage

Do not store above 30 °C.

Store in the original packaging blister in order to protect from moisture.

10. Date of revision of the text

November 2022 November 2023

REC20788+REC30040_BP23003

Note:

Text in black = unchanged text

Text in blue = added text

Text in red with strikethrough = deleted text

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”.] 

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 warnings and precautions for use:

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

6.4 Special precautions for storage

Do not store above 30 °C.

Store in the original packaging blister in order to protect from moisture.

10. Date of revision of the text

November 2022 November 2023

REC30965, BP22056

Note:

Text in black = unchanged text

Text in blue = added text

Text in red with strikethrough = deleted text

4.3 Contraindications

[….]

Yasmin 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, Yasmin-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. Yasmin 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:

Text in black = unchanged text

Text in blue = added text

Text in red with strikethrough = deleted text

2. What you need to know before you take Yasmin

[….]

Do not use Yasmin 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 Yasmin”).

[….]

Other medicines and Yasmin

Do not use Yasmin 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 October 2022 November 2022.

Administrative changes. BP: NA. REC: NA.

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

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, Bulgaria, Croatia, Cyprus, Denmark, Finland, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Spain, Sweden, United Kingdom: Yasmin

·     France: Jasmine

·     Czechia, Hungary, Slovakia: Yadine

·     Estonia, Latvia, Lithuania, Slovenia: Yarina

This leaflet was last revised in September October 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, The Atrium, Blackthorn road, Dublin 18, Ireland

[….]

This leaflet was last revised in November 2021September 2022.

[….]

BP22036, REC30610

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

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

What is in this leaflet

[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 Yasmin

[…]

Do not use Yasmin 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 Yasmin”).

[…]

Other medicines and Yasmin

[…]

Do not use Yasmin 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 Yasmin looks like and content of the pack

[…]

• Yasmin tablets are film-coated tablets; the core of the tablet is coated. The tablets are light yellow, round with convex surfaces, one side is embossedmarked with the letters "DO" in a regular hexagon.

[…]

This leaflet was last revised in March 2021November 2021.

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 yellow, round tablets with convex faces, one side embossedmarked with the letters "DO" in a regular hexagon

[…]

4.3 Contraindications

[…]

Yasmin 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 2021April 2021

File name of SmPC corrected.

(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

April 2021July 2021

Summary of Changes to the SmPC

6.4         Special precautions for storage

[….]

Do not store above 3025 °C

[….]

7            MARKETING AUTHORISATION HOLDER

Bayer Limited

The Atrium

Blackthorn Road

Dublin 18

Ireland

10           Date of Revision of text

August 2020 April 2021

Summary of Changes to the Patient Information leaflet:

5.         How to store Yasmin

[….]

Do not store above 3025 °C. Store in the original package.

[….]

6.         Contents of the pack and other information

Marketing Authorisation Holder

Bayer Limited, The Atrium, Blackthorn Road, Dublin 18, Ireland

[….]

This leaflet was last revised in March 2021 August 2020.

Reason for change:

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

Section 1: What Yasmin 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 Yasmin

[….]

Additional information on special populations

Use in cChildren and adolescents
Yasmin is not intended for use in females whose periods have not yet started.

Use in Older women
Yasmin is not intended for use after the menopause.

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

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

Section 3: How to take Yasmin

[….]

The strip contains 21 film-coated tablets.

[….]

Section 4 Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below).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. By reporting side effects you can help provide more information on the safety of this medicine.

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

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, Croatia, Cyprus, Denmark, Finland, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, United Kingdom: Yasmin

[….]

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

Reason for change:

• Addition of lactose monohydrate value in section 2 of the SmPC
• Additional information on special populations included in section 4.2.
• HPRA details for Reporting of suspected adverse reactions updated.
• Editorial updates included

Section 2: QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 0.030 mg ethinylestradiol and 3 mg drospirenone

Excipient with known effect: lactose 46 mg (as lactose monohydrate 48.17 mg)

[….]

Section 4.2: Posology and method of administration

[….]

Additional information on special populations

Children and adolescents Paediatric population

Yasmin is only indicated after menarche. Based on epidemiological data collected on more than 2000 adolescent women aged below 18 years, there are no data indicating that safety and efficacy in this young age group is different from that known in women aged above 18 years.

Elderly

Yasmin is not indicated after menopause.

Patients with hepatic impairment

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

Patients with renal impairment

Yasmin 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

[….]

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

[….]

Section 4.8 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

The text below in red has been added.

4.3 Contraindications

[…]

Yasmin 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, Yasmin 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. Yasmin 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 Yasmin. 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 4.5:

………………

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 Yasmin 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 metabolised completely (metabolic plasma clearance 5 ml/min/kg). Ethinylestradiol is subject to 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:

1.1                Interaction with other medicinal products and other forms of interaction

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

·     Influence Effects of other medicinal products on Yasmin

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.

Substances 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:

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.

Interference with Enterohepatic Circulation

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 Yasmin 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 Yasmin 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.

1.8                Undesirable effects

…

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.

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).

9.                DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 27 October 2000

Date of latest renewal: 7 March 20102015

10.            DATE OF REVISION OF THE TEXT

September 2014January 2015

2.     QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 0.030 mg ethinylestradiol and 3 mg drospirenone

Excipient with known effect: lactose 46 mg

For athe full list of excipients, see section 6.1.

3.     PHARMACEUTICAL FORM

Film-coated tablets

Light yellow, round tablets with convex faces, one side embossed with the letters "DO" in a regular hexagon

4.                   CLINICAL PARTICULARS

4.1 Therapeutic indications

Oral contraception

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

4.2  Posology and method of administration

Method of administration

Route of administration: oOral use

Posology

…

Additional information on special populations

Children and adolescents

Yasmin is only indicated after menarche. Based on epidemiological data collected on more than 2000 adolescent women aged below 18 years, there are no data indicating that safety and efficacy in this young age group is different from that known in women aged above 18 years.

4.3 Contraindications

Combined oralhormonal contraceptives (COCsCHCs) should not be used in the presence of any of thefollowing conditions listed below.. Should any of the conditions appear for the first time during COCCHC use, the product should be stopped immediately.

·       Presence or risk of venous thromboembolism (VTE)

o   Venous thrombosis present or in 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 thrombosis present or inthromboembolism – current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal conditionscondition (e.g. angina pectoris and )

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

·       Cerebrovascular accident present or in history

o   TheKnown 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 a severe or multipleone serious risk factor(s) for arterial thrombosis such as:

·       diabetes mellitus with vascular symptoms

·       severe hypertension

·       severe dyslipoproteinemiadyslipoproteinaemia

·       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 Yasmin film-coated tabletslisted in section 6.1.

4.4 Special warnings and precautions for use

Warnings

·       If any of the conditions/ or risk factors mentioned below is present, the benefitssuitability of COC useYasmin 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 be advised to contact her physician. The physician should then decide ondoctor to determine whether COCthe use of Yasmin 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).

·       Circulatory Disorders

Risk of venous thromboembolism (VTE)

The use of any combined oralhormonal contraceptive (COC) carries an increased CHC) increases the risk of venous thromboembolism (VTE) compared with no use. The excessProducts that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as Yasmin 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 Yasmin, how her current risk factors influence this risk, and that her VTE risk is highest duringin the first year a woman initially starts using a COC or ever year of use. There is also some evidence that the risk is increased when she restarts COC use a CHC is re-started after a pill-free interval of at least a monthbreak in use of 4 weeks or more.

Epidemiological studies have shown that the incidence of VTE in In women with no known risk factors for VTE who do not use low dose oestrogen (<50 µg ethinylestradiol) combined oral contraceptives ranges froma CHC and are not pregnant, about 20 cases per 1002 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman-years (for the risk may be far higher, depending on her underlying risk factors (see below).

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 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 is CHC.

In both cases, the number of VTEs per year is fewer than the number expected during pregnancy or in the postpartum period.

VTE may be fatal in 1-2% of the cases.

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.

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

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..

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.

Risk factors for VTE

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

·       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)

thereYasmin 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 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

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 pregnancy, and particularly the 6-week period of the puerperium, must be considered (for information on "“Pregnancy and Lactation"lactation” see section 4.6).

Other Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

In the event of symptoms women should be advised to seek urgent medical conditionsattention 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 have been 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 adversehaemoptysis;

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

An increase in frequency or severityIf the occlusion occurs in the eye symptoms can range from painless blurring of migraine during COC use (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 prodromalfatal.

Risk factors for ATE

The risk of arterial thromboembolic complications or of a cerebrovascular event) mayaccident in CHC users increases in women with risk factors (see table). Yasmin 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 a reason for immediate discontinuation of the COCconsidered. 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.

…

Medical examination/consultation

Prior to the initiation or reinstitution of Yasmin 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 Yasmin 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 oralhormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Reduced efficacy

The efficacy of COCs may be reduced in the event of e.g. missed tablets (see section 4.2), gastro-intestinal disturbances (see section 4.2) or concomitant medication (see section 4.5).

Reduced cycle control

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.

If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.

In some women withdrawal bleeding may not occur during the tablet-free interval. If the COC has been taken according to the directions described in section 4.2, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.

4.6  Fertility, pPregnancy and lactation

Pregnancy

Yasmin is not indicated during pregnancy.

If pregnancy occurs during use of Yasmin, 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 Yasmin during pregnancy are too limited to permit conclusions concerning negative effects of Yasmin 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 Yasmin (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 Yasmin:

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 following serious adverse events have been reported in women using COCs, which are discussed in section 4.4 Special warningwarnings 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 OCCOC 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.

5                 PHARMACOLOGICAL PROPERTIES

5.2  Pharmacokinetic properties

·       Drospirenone

MetabolismBiotransformation

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

MetabolismBiotransformation

Ethinylestradiol is metabolised completely (metabolic plasma clearance 5 ml/min/kg).

6                 PHARMACEUTICAL PARTICULARS

6.6  Instructions for use and handlingSpecial precautions for disposal

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

9       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 27 October 2000

Date of latest renewal: 7 March 2010

10              DATE OF REVISION OF THE TEXT

September 2014

2.     QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 0.030 mg ethinylestradiol and 3 mg drospirenone

Excipient with known effect: lactose 46 mg

For athe full list of excipients, see section 6.1.

3.     PHARMACEUTICAL FORM

Film-coated tablets

Light yellow, round tablets with convex faces, one side embossed with the letters "DO" in a regular hexagon

4.                 CLINICAL PARTICULARS

4.2  Posology and method of administration

Method of administration

Route of administration: oOral use

Posology

…

Additional information on special populations

Children and adolescents

Yasmin is only indicated after menarche. Based on epidemiological data collected on more than 2000 adolescent women aged below 18 years, there are no data indicating that safety and efficacy in this young age group is different from that known in women aged above 18 years.

4.3 Contraindications

·       Hypersensitivity to the active substances or to any of the excipients of Yasmin film-coated tabletslisted in section 6.1.

4.6  Fertility, pPregnancy and lactation

Pregnancy

Yasmin is not indicated during pregnancy.

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

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 Yasmin:

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

MetabolismBiotransformation

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

MetabolismBiotransformation

Ethinylestradiol is metabolised completely (metabolic plasma clearance 5 ml/min/kg).

6               PHARMACEUTICAL PARTICULARS

6.6  Instructions for use and handlingSpecial precautions for disposal

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

9      DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 27 October 2000

Date of latest renewal: 7 March 2010

10            DATE OF REVISION OF THE TEXT

July 2014

• Pancreatitis or a history thereof if associated with severe hypertriglyceridemia

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

April 2013

(Inserted text; deleted text)

4.4                Special warnings and precautions for use

Warnings

…………………………………..

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).

……………………………………

4.8          Undesirable effects

For serious undesirable effects in COC users see section 4.4.

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

………………………………………

-               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;

10.          DATE OF REVISION OF THE TEXT

June 2011May 2012

"According to two epidemiological studies published in 2009, one retrospective cohort study (Lidegaard et al.) and one case control study (van Hylckama Vlieg et al.), the risk of venous thromboembolism occurring in Yasmin users was between those for levonorgestrel-containing COCs (so-called second generation COCs) and desogestrel/gestodene-containing COCs (so called third generation COCs).

One prospective cohort study (EURAS) showed the risk of venous thromboembolism in Yasmin users to be comparable to that of so-called second generation preparations. A further prospective cohort study (Ingenix) showed a comparable risk of thrombosis in Yasmin users and other COC users, including levonorgestrel."

and the following text has been added:
"Epidemiological studies have shown that the risk of VTE for drospirenone-containing OCs is higher than for levonorgestrel-containing OCs (so-called second generation preparations) and may be similar to the risk for desogestrel/gestodene-containing OCs (so-called third generation preparations)."

In section 10, "June 2011" has been inserted as date of revision of text.

Changes to SPC as a result of renewal application approval.

4.4              Special warnings and precautions for use

Under subheading “Warnings”

Deletion of :

“Data from a large, prospective 3-armed cohort study has shown that the incidence of VTE in women with or without other risk factors for VTE who used Yasmin is in the same range as that for users of other low dose oestrogen combined oral contraceptives, including levonorgestrel-containing OCs (so-called ‘second’ generation OCs).”

Insertion of:

“According to two epidemiological studies published in 2009, one retrospective cohort study (Lidegaard et al.) and one case control study (van Hylckama Vlieg et al.), the risk of venous thromboembolism occurring in Yasmin users was between those for levonorgestrel-containing COCs (so-called second generation COCs) and desogestrel/gestodene-containing COCs (so called third generation COCs).

One prospective cohort study (EURAS) showed the risk of venous thromboembolism in Yasmin users to be comparable to that of so-called second generation preparations. A further prospective cohort study (Ingenix) showed a comparable risk of thrombosis in Yasmin users and other COC users, including levonorgestrel.”

4.8              Undesirable effects

Addition of rare adverse event “hypersensitivity”, “erythema nodosum” and “erythema multiforme”

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

“7 March 2010” inserted as date of last renewal

10.       DATE OF REVISION OF THE TEXT

“September 2010” inserted as date

"Epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low oestrogen content (<50 µg ethinylestradiol) (including Yasmin) ranges from about 20 to 40 cases per 100,000 woman-years, but this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 woman-years for non-users.

Section 7. Marketing Authorisation Holder

The Marketing Authorisation Holder was changed from "HE Clissmann, Dublin." to "Bayer Limited, The Atrium, Blackthorn Road, Dublin 18.".

Section 8. Marketing Authorisation Number(s)

The PA number was changed from "PA 12/91/1" to "PA 1410/23/1".

Section 10. Date of Revision of the Text

The date was changed from "September 2006" to "October 2007".

SECTION 4.2 POSOLOGY AND METHOD OF ADMINISTRATION

Updated data regarding the start of treatment with Yasmin following use of a progestogen-only contraceptive method.

SECTION 4.3 CONTRAINDICATIONS

Addition of a contraindication: ‘Pancreatitis or a history thereof if associated with severe hypertriglyceridemia’.

SECTION 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Changes to the following sections:        

Circulatory disorders

• addition of the following risk factors for arterial thromboembolic complications or for cerebrovascular accident

-         migraine

-         obesity

-         positive family history (arterial thromboembolism ever in a sibling or parent at a relatively early age)

·         addition of sickle cell disease to the list of other medical conditions associated with adverse vascular events

Other conditions

·         new information regarding the effect of Yasmin on serum potassium levels

·         addition of the following warning: ‘In women with hereditary angioedema exogenous estrogens may induce or exacerbate the symptoms of angioedema’.

SECTION 4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Changes to the following sections: 

Influence of other medicinal products on Yasmin

·         new advice regarding women on chronic treatment with hepatic enzyme inducing drugs: reliable, non-hormonal contraceptive method of contraception is recommended

Influence of Yasmin on other medicinal products

·         new information regarding the effect of oral contraceptives on the metabolism of other active substances. This may influence the plasma and tissue concentrations of certain drugs e.g. cyclosporin, lamotrigine

SECTION 4.8 UNDESIRABLE EFFECTS

Addition of the following adverse effect: ‘In women with hereditary angioedema exogenous estrogens may induce or exacerbate the symptoms of angioedema’.

SECTION 5.1 PHARMACODYNAMIC PROPERTIES

Updated ATC code.

SECTION 5.2 PHARMACOKINETIC PROPERTIES

Changes to the following section: 

Drospirenone

·         new information regarding the maximum serum levels of drospirenone after single ingestion

·         new information regarding the terminal half life of serum drospirenone

·         new information regarding the metabolism of drospirenone by cytochrome P450 3A4 and the demonstration of the ability of drospirenone to inhibit this enzyme and cytochrome P450 1A1, cytochrome P450 2C9 and cytochrome P450 2C19 in vitro.

·         new information regarding the maximum steady state concentration of drospirenone in serum

·         new information regarding the properties of drospirenone in special populations (renal impairment, hepatic impairment, ethnic groups)