REC20788+REC30040_BP23002

Note:

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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 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

REC20788+REC30040_BP23002

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 Yaz

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 pharynx and/or difficulty swallowing or hives together with difficulty breathing.

3. How to take Yaz

Preparation of the strip

[…..]

Stick the week sticker along the top of the Yaz strip where it reads “Place week sticker here”, so that the first day is above the tablet marked “Start1”.

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”).

6.                  Contents of the pack and other information

What Yaz contains

See section 2 “Yaz contains lactose”.

[….]

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

·        Bulgaria, Czech Republic, Estonia, France, Germany, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Poland, Romania, Slovak Republic, Slovenia, Spain: YAZ

·        Austria, Belgium, Croatia, Finland, Luxembourg, Norway, Portugal, Sweden: Yaz

·        Netherlands: YAZ 24+4

This leaflet was last revised in November 2022 May 2023.

REC30965, BP22056

Note:

Text in black = unchanged text

Text in blue = added text

Text in red with strikethrough = deleted text

4.3 Contraindications

[….]

YAZ 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, YAZ 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. YAZ 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 Yaz

[….]

Do not use Yaz 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 Yaz”).

[….]

Other medicines and Yaz

Do not use Yaz 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, 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

[BP21028_BEC19714+19965]

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

PIL

2. What you need to know before you take Yaz

[…]

Do not use Yaz 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 Yaz”).

[…]

Other medicines and Yaz

[…]

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

[…]

• The active tablet is light pink, round with convex surfaces; one side is markedembossed with the letters “DS” in a regular hexagon.
• The placebo tablet is white, round with convex surfaces; one side is markedembossed with the letters “DP” in a regular hexagon.

[…]

This leaflet was last revised in August 2020November 2021.

[BP21028_BEC19714+19965]

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

3. PHARMACEUTICAL FORM

Film-coated tablets

The active tablets are light pink, round with convex faces, one side markedembossed with the letters “DS” in a regular hexagon.

The placebo tablets are white, round with convex faces, one side markedembossed with the letters “DP” in a regular hexagon.

[…]

4.3 Contraindications

[…]

YAZ 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 section 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

"Ireland" was added to the Marketing authorisation holder address. 

"Ireland" was added to the Marketing Authorisation Holder address. 

The date of revision was updated to "July 2021".

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

[….]

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

[….]

Excipient with known effect: lactose 22 mg (as lactose monohydrate 23.21 mg)

[….]

Section 4.2: Posology and method of administration

[….]

Additional information on special populations

Paediatric population

Yaz is only indicated after menarche.

Elderly

Yaz is not indicated after menopause.

Patients with hepatic impairment

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

Patients with renal impairment

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

[….]

Each light pink film-coated tablet of this medicinal product contains 46 mg lactose per tablet, each white film-coated tablet contains 22 mg.

[….]

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 Yaz is and what it is used for

[….]

• Each of the 24 light pink film-coated tablets contains a small amount of two different female hormones, namely drospirenone and ethinylestradiol.
• The 4 white film-coated tablets contain no active substances and are also called placebo tablets.

 [….]

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

[….]

Additional information on special populations

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

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

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

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

Section 3: How to take Yaz

Each blister contains 24 active light pink film-coated tablets and 4 white placebo 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:

• Bulgaria, Czech Republic, Estonia, France, Germany, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Poland, Romania, Slovak Republic, Slovenia, Spain: YAZ
• Austria, Belgium, Croatia, Denmark, Finland, Norway, Portugal, Sweden: Yaz

[….]

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

The text below in red has been added.

4.3 Contraindications

[…]

Yaz 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, YAZ-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. YAZ 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 YAZ. 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.

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.

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:

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

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal.

[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 YAZ 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 and 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 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’

2.                QUALITATIVE AND QUANTITATIVE COMPOSITION

24 light pink film-coated tablets:
Each film-coated tablet contains 0.020 mg ethinylestradiol (as betadex clathrate) and 3 mg drospirenone.

Excipient with known effect: lactose 46 mg

4 white placebo (inactive) film-coated tablets:
The tablet does not contain active substances.

Excipient with known effect: lactose 22 mg

For the full list of excipients, see section 6.1.

3.                PHARMACEUTICAL FORM

Film-coated tablets

The active tablets is are light pink, round with convex faces, one side embossed with the letters "DS" in a regular hexagon.

The placebo tablets is are white, round with convex faces, one side embossed with the letters "DP" in a regular hexagon.

4.                CLINICAL PARTICULARS

4.2            Posology and method of administration

MethodRoute of administration: oral use

Posology

Dosage regimen

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 YAZ

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 active tablets in the COC pack, the placebo tablets must be discarded and the next COC pack should be started right away.

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.

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 active tablets in the current COC blister pack, the placebo tablets must be discarded and the next COC pack should be started right away.

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 YAZ 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 YAZ 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.

4.8            Undesirable effects

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

…

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).

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.

10.            DATE OF REVISION OF THE TEXT

September 2014January 2015

4.     CLINICAL PARTICULARS

4.1  Therapeutic indications

Oral contraception.

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

4.3 Contraindications

Combined oral hormonal contraceptives (CHOCs) should not be used in the presence of any of the following conditions listed below. Should any of the conditions appear for the first time during COHC 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 listed 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 suitability of YAZ 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 YAZ 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 (CHC) increases 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 YAZ 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 YAZ, 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.

The use of any combined oral contraceptive (COC) carries an increased risk of venous thromboembolism (VTE) compared with no use. 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.

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).Epidemiological studies have shown that the incidence of VTE in women with no known risk factors for VTE who use low dose oestrogen (<0.05 mg 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 is fatal in 1-2% of cases.

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.

VTE may be 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).

YAZ 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.

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:

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

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

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

Symptoms of pulmonary embolism (PE) can include:

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

o  sudden coughing which may be associated with haemoptysis;

o  sharp chest pain;

o  severe light headedness or dizziness;

o  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.

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 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.

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). YAZ 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:

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

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

o  sudden confusion, trouble speaking or understanding;

o  sudden trouble seeing in one or both eyes;

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

o  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:

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

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

o  feeling of being full, having indigestion or choking;

o  sweating, nausea, vomiting or dizziness;

o  extreme weakness, anxiety, or shortness of breath;

o  rapid or irregular heartbeats.

…

Medical examination/consultation

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

4.6  Fertility, pregnancy and lactation

Pregnancy

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

4.8  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.

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

2.      QUALITATIVE AND QUANTITATIVE COMPOSITION

4 white placebo (inactive) film-coated tablets:
The tablet does not contain active substances.

Excipient: lactose 50 mg22 mg

For the full list of excipients, see section 6.1.

4.4 Special warnings and precautions for use

Warnings

·         Other conditions

Each light pink tablet of this medicinal product contains 46 mg lactose per tablet, each white tablet contains 50 mg22 mg. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this amount into consideration.

6.1 List of excipients

10. DATE OF REVISION OF THE TEXT

April 2013 May 2014

Deleted Text = Red strike through

New Text = Bold green italics

Text present in full SmPC not included here = …………………………

Section 4.2 Posology and method of administration

………………………………………………………………………………………………………………

Management of missed tablets

Placebo tablets from the last (4^th) row of the blister can be disregarded. However, they should be discarded to avoid unintentionally prolonging the placebo tablet phase. The following advice only refers to missed active tablets:

If the user is less than 2412 hours late in taking any tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.

If she is more than 2412 hours late in taking any tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:

1.    the recommended hormone-free tablet interval is 4 days, tablet-taking must never be discontinued for longer than 74 days

2.    7 days of uninterrupted tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.

………………………………………………………………………………………………………………

Advice in case of gastro-intestinal disturbances

In case of severe gastro-intestinal disturbances (e.g., vomiting or diarrhoea), absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after active tablet-taking, a new (replacement) tablet should be taken as soon as possible. The new tablet should be taken within 2412 hours of the usual time of tablet-taking if possible. If more than 2412 hours elapse, the advice concerning missed tablets, as given in section 4.2 “Management of missed tablets”, is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) from another blister pack.

………………………………………………………………………………………………………………

Section 10 Date of Revision of the Text

December 2012

January 2013

[Inserted text; Deleted text]

Section 2: QUALITATIVE AND QUANTITATIVE COMPOSITION

…………………..

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

Section 4.3: Contraindications

…………………..

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

Section 4.4: Special warnings and precautions for use

……………………..

·         Circulatory Disorders

The use of any combined oral contraceptive (COC) carries an increased risk of venous thromboembolism (VTE) compared with no use. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive. initially starts using a COC or when she restarts COC use after a pill-free interval of at least a month.

Epidemiological studies have shown that the incidence of VTE in women with no known risk factors for VTE who use low dose oestrogen (<0.05 mg 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 is fatal in 1-2% of 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).

………………

Section 4.6: Fertility, pregnancyPregnancy and lactation

Pregnancy

YAZ is not indicated during pregnancy.

If pregnancy occurs during use of with YAZ, 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 adverse effect in humans.

The available data regarding the use of YAZ during pregnancy are too limited to permit conclusions concerning negative effects of YAZ 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.

Fertility

YAZ is indicated for the prevention of pregnancy. For information on return to fertility, see section 5.1.

Section 4.8: Undesirable effects

……………………….

……………………………………………

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 5.1: Pharmacodynamic properties

Pharmacotherapeutic group (ATC): Progestogens and estrogens, fixed combinations
ATC Code: G03AA12

Pearl Index for method failure: 0.41 (upper two-sided 95 % confidence limit: 0.85).
Overall Pearl Index (method failure + patient failure): 0.80 (upper two-sided 95% confidence limit: 1.30).

The contraceptive effect of YAZ is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the endometrium.

In a 3-cycle ovulation inhibition study comparing drospirenone 3 mg / ethinylestradiol 0.020 mg in a 24-day-regimen and a 21-day-regimen, the 24-day-regimen was associated with greater suppression of follicular development. After intentionally introduced dosing errors during the third cycle of treatment, a greater proportion of women in the 21-day-regimen showed ovarian activity including escape ovulations compared to the women taking the 24-day-regimen. Ovarian activity returned to pre-treatment levels during the post-treatment cycle in 91.8% of the women who took the 24-day regimen.

Section 9: DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17th October 2008

Date of last renewal: 29^th June 2012

Section 10: DATE OF REVISION OF THE TEXT

June 2011 December 2012

In section 4.4 (Special warnings and precautions for use):
the following test has been deleted:

"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 drospirenone/ethinylestradiol 3 mg / 0.03 mg 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 drospirenone/ethinylestradiol 3 mg/ 0.03 mg 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 drospirenone/ethinylestradiol 3 mg/ 0.03 mg users and other COC users, including levonorgestrel. The VTE risk of YAZ is currently unknown.

"

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.

New text = green, bold italics. Deleted text = red, strike-through

4.4  Special warnings and precautions for use

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 ethinylestradiol / drospirenone 0.03 mg / 3 mg 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). 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 drospirenone/ethinylestradiol 3 mg / 0.03 mg 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 drospirenone/ethinylestradiol 3 mg/ 0.03 mg 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 drospirenone/ethinylestradiol 3 mg/ 0.03 mg users and other COC users, including levonorgestrel.

4.8 Undesirable effects

not known (cannot be estimated from the available data): Hypersensitivity,  Erythema multiforme

10. DATE OF REVISION OF THE TEXT

November 2010

6.5 Nature and contents of container

YAZ 0.02 mg / 3 mg film-coated tablets