Dianette 2mg/35 microgram coated tablets

BP22046 REC30885: Article 61.3 notification

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

6. Contents of the pack and other information

[…]

Manufacturer:

The manufacturer can be identified by the batch number printed on the carton and on each blister:

• If the first and second characters are KT, the manufacturer is:

Bayer AG

Müllerstraße 178

1334253 Berlin

Germany

• If the first and second characters are WE, the manufacturer is:

Bayer Weimar GmbH und Co. KG

Döbereinerstraße 20

99427 Weimar

Germany                                                    

This leaflet was last revised in February 2023 October 2022

BP22055, REC30965

Implementation of the outcome of PSUSA on chlormadinone acetate/ethinylestradiol: In the framework of the PSUSA on chlormadinone acetate / ethinylestradiol (PSUSA/00000679/202111) PRAC considered that the risk of elevated liver enzymes would also be relevant to be included in products containing ethinylestradiol as a single agent or in fixed dose combinations as the risk of elevated liver enzymes is associated with concomitant use of ethinylestradiol and sofosbuvir/velpatasvir/voxilaprevir.

Note:

Text in blue = added

Text in red strikethrough = deleted

Package Leaflet

2. What you need to know before you take Dianette

[...]

Do not take Dianette 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 Dianette”).

 [...]

Other medicines and Dianette

Do not take Dianette 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 this may cause increases in liver function blood test results (increase in ALT liver enzyme). Your doctor will prescribe another type of contraceptive prior to start of the treatment with these medicinal products. Dianette can be restarted approximately 2 weeks after completion of this treatment. See section “Do not take Dianette”.

[...]

BP22055, REC30965

Implementation of the outcome of PSUSA on chlormadinone acetate/ethinylestradiol: In the framework of the PSUSA on chlormadinone acetate / ethinylestradiol (PSUSA/00000679/202111) PRAC considered that the risk of elevated liver enzymes would also be relevant to be included in products containing ethinylestradiol as a single agent or in fixed dose combinations as the risk of elevated liver enzymes is associated with concomitant use of ethinylestradiol and sofosbuvir/velpatasvir/voxilaprevir.

Note:

Text in blue = added

Text in red strikethrough = deleted

Summary of Product Characteristics

[...]

4.3 Contraindications

Dianette 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

Other conditions

[...]

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).

[...]

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

[...]

BP22034, BEC20788

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

2. What you need to know before you take Dianette

[…]

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 estrogens 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

An increased risk of blood clots in your veins (venous thromboembolism (VTE)) or blood clots in your arteries (arterial thromboembolism (ATE)) is present for all women taking combined hormonal contraceptives. For more detailed information on the different risks from taking combined hormonal contraceptives please see section 2 “What you need to know before you take Dianette”.

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”).

[…]

If you have hereditary angioedema medicines containing certain female sex hormones (oestrogens) may induce or worsen the symptoms of angioedema (see section “What you need to know before you take Dianette”).

[…]

6. Contents of the pack and other information

[…]

This leaflet was last revised in: October 2022December 2021

BP22034, BEC20788

Note:

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 exogenous estrogens may induce or exacerbate symptoms of angioedema

Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema

[…]

*The most appropriate MedDRA term (version 12.0) to describe a certain adverse reaction is listed.

Synonyms or related conditions are not listed, but should be taken into account as well.

4.8.3 Description of selected adverse reactions

[…]

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.

10. DATE OF REVISION OF THE TEXT

OctoberSeptember 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 SeptemberDecember 2021

BP22036, REC30610

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

7. MARKETING AUTHORISATION HOLDER

Bayer Limited

1^st 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 THE TEXT

September2022December2021

Updates required following CMDh request regarding the pharmacodynamic drug-drug interaction between ethinylestradiol and Maviret (glecaprevir/pibrentasivir) as noted by PRAC in the framework of the PSUSA on ethinylestradiol/etonogestrel.

Updates required following CMDh request regarding the pharmacodynamic drug-drug interaction between ethinylestradiol and Maviret (glecaprevir/pibrentasvir) as noted by PRAC in the framework of the PSUSA on ethinylestradiol/etonogestrel.

Editorial change to the PA number (PA 1410/003/001) listed in section 8: Marketing Authorisation number. The space between "PA" and "1410" has been deleted. So the PA number now appears as PA1410/003/001.

• Amendment of the excipient warning information currently in the PIL for sucrose and lactose, in order to fully align with the Annex to the European Commission guideline on "Excipients in the labelling and package leaflet of medicinal products for human use" (EMA/CHMP/302620/2017 Rev. 1, Pursuant to Article 65 of Directive 2001/83/EC): Section 2: Dianette contains lactose and sucrose If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal productDianette.
• Update of the PIL in order to align to the current QRD template (version 10.1).

• Amendment of the excipient warning information currently in the SmPC for sucrose and lactose, in order to fully align with the Annex to the European Commission guideline on "Excipients in the labelling and package leaflet of medicinal products for human use" (EMA/CHMP/302620/2017 Rev. 1, Pursuant to Article 65 of Directive 2001/83/EC): Section 4.4: Each coated tablet of Tthis medicinal product contains sucrose and 31 mg lactose per tablet. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.who are on a lactose-free diet should take the lactose content into account.

• Update of the SmPC in order to align to the current QRD template (version 10.1).

Updated as a result of PRAC recommendation - risk of meningioma with cyproterone acetate containing medicinal products. Published and endorsed by CHMP 26 March 2020.

Change to section 2 - What you need to know before you take Dianette:

<The following sentence has been added to the “Do not use Dianette” section>

Do not use Dianette:

[……….]

if you have meningioma or have ever been diagnosed with a meningioma (a generally benign tumour of the tissue layer between the brain and the skull)

[……….]

<The following sentence has been added to the “Warnings and Precautions” section>

Warnings and precautions

[……….]

Meningioma

For high doses (25 mg and above) of cyproterone acetate an increased risk of a benign brain tumour (meningioma) has been reported. If you are diagnosed with meningioma, your doctor will stop all cyproterone containing products, including Dianette as a precautionary measure (see section ‘Do not use Dianette’).

[……….]

Change to section 4 – how to report a side effect:

<The HPRA contact details for the reporting of side effects were updated>

[……….]

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly 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.

[……….]

Change to section 6 - date of revision:

<The revision date of the leaflet was updated to state>

April 2019 May 2020

Updated as a result of PRAC recommendation - risk of meningioma with cyproterone acetate containing medicinal products. Published and endorsed by CHMP 26 March 2020.

Change to section 4.3 - Contraindications:

<The following was added to section 4.3 Contraindications>

[……….]

• Meningioma or history of meningioma.

[……….]

Change to section 4.4 - Special warning and precautions for use:

<The following was added to section 4.4 Special warning and precautions for use>

[……….]

Meningioma

The occurrence of meningiomas (single and multiple) has been reported in association with use of cyproterone acetate, especially at high doses of 25 mg and above and for prolonged time (see section 5.1). If a patient is diagnosed with meningioma, any cyproterone containing treatment, including Dianette must be stopped, as a precautionary measure

[……….]

Change to section 4.8 – Undesirable effects:

 <The HPRA contact details for the reporting of side effects were updated>

[……….]

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.

[……….]

Change to section 5.1 - Pharmacodynamic properties:

<The following was added to section 5.1 Pharmacodynamic properties>

[……….]

Meningioma
Based on results from a French epidemiological cohort study, a cumulative dose-dependent association between cyproterone acetate and meningioma has been observed. This study was based on data from the French Health insurance (CNAM) and included a population of 253,777 women using 50 - 100 mg cyproterone tablets. The incidence of meningioma treated with surgery or radiotherapy was compared between women exposed to high-dose cyproterone acetate (cumulative dose ≥3 g) and women who were slightly exposed to cyproterone acetate (cumulative dose <3 g). A cumulative dose-response relationship was demonstrated.

^a Adjusted based on age as a time-dependent variable and oestrogen at inclusion

A cumulative dose of 12g for example can correspond with one year of treatment with 50 mg/day for 20 days each month.

[……….]

Change to section 10 – Date of revision of the text

<The revision date of the SPC was updated to:>

April 2019 May 2020

Updated as a result of PRAC recommendation - signal on hormonal contraceptives/ suicidality published and endorsed by CHMP 29 October 2019

SPC updated in line with new PRAC update regarding depression

Section 4.4

Depressed mood and depression

Depressed mood and depression are well-known undesirable effects of hormonal

contraceptive use (see section 4.8). Depression can be serious and is a well-known

risk factor for suicidal behaviour and suicide.

Women should be advised to contact their physician in case of mood changes and

depressive symptoms, including shortly after initiating the treatment.

Updates to section 4.5 'Interaction with other medicinal products and other forms of interaction' (additional information):

Substances decreasing the clearance of CHC (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.

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 estrogen/progestogen combinations on other medicinal products (additional information):

Clinical data suggest 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.

Updates to section 4.8 Undesirable effects:

4.8.1 Summary of safety profile

The most commonly reported adverse reactions with Dianette are nausea, abdominal pain, increased weight, headache, depressed mood, altered mood, breast pain, breast tenderness. They occur in ≥ 1 % of users.

There is an increased risk of thromboembolism for all women who use Dianette (see section 4.4).

Formatting changes to section 4.8.2 ‘Tabulated list of adverse reactions’:

Inclusion of MedDRA under System Organ Class

Updates to Section 4.8.3 ‘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 CHCs, which are discussed in section 4.4 Special warnings and precautions for use:

- Venous thromboembolic disorders;

- Arterial thromboembolic disorders;

- Hypertension;

- Liver tumors;

- 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.

Updates to section 5.2 ‘Pharmacokinetic properties’:

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.

Changes in section 4.5 - addition of paragraph 'substances decreasing the clearance of CHC (enzyme inhibitors)', addition of paragraph on clinical data supporting CYP1A2 interaction.

Change in section 4.8 - addition of paragraph under heading 4.8.1 Summary of safety profile, formatting changes to section 4.8.3 description of selected adverse reactions.

Change in section 5.2 - addition of enzyme interactions for ethinylestradiol.

The text below in red has been added.

4.3 Contraindications

[…]

Dianette 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

[…]

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.

[…]

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, Dianette-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. Dianette can be restarted 2 weeks following completion of treatment with this combination drug regimen.

4.9 Overdose

There have been no reports of serious deleterious effect from overdose. Symptoms that may occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding, 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.

“Other conditions

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

Although small increases in blood pressure have been reported in many women taking COCs or Dianette, clinically relevant increases are rare….”

Section 4.8:

……………………

……………………

 
Section 10: Date of revision changed from 'December 2014' to 'July 2015'

4.2. Posology and method of administration

How to start Dianette

The woman should start with Dianette preferably on the day after the last hormone-containing tablet of her previous COC, but at the latest on the day following the usual tablet-free or hormone-free tablet interval of her previous COC.

If a vaginal ring or transdermal patch has been used, the woman should, preferably, start using Dianette on the day of removal of the last ring or patch of a cycle pack, but at the latest when the next application would have been due.

·         Following first-trimester abortion

The woman may start immediately. When doing so, she need not takedoes not need additional contraceptive measures.

4.4 Special warnings and precautions for use

Arterial thromboembolic events may be life-threatening or may have a fatal outcome.

The potential for an increased synergistic risk of thrombosis should be considered in women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increased risk may be greater than a simple cumulative risk of the factors. Dianette should not be prescribed in case of a negative risk benefit assessment. (see section 4.3 ‘Contraindications’)

Tumors

Malignancies may be life-threatening or may have a fatal outcome.

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.

Effects of other medicaments on Dianette

Interactions of other drugs (enzyme inducers, some antibiotics) with estrogen/progestogen combinations like Dianette Interactions may 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. Women on treatment with any of these drugs should temporarily use a barrier method in addition to Dianette or choose another method of contraception. With microsomal enzyme-inducing drugs, tThe barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation.

Women on treatment with antibiotics (except rifampicin and griseofulvin) should use the barrier method until 7 days after discontinuation. If the period during which the barrier method is used runs beyond the end of the tablets in the Dianette pack, the next pack should be started without the usual tablet-free interval.

Substances diminishing the efficacy of Dianette (enzyme-inducers and antibiotics)Substances increasing the clearance of Dianette (diminished efficacy of Dianette by enzyme-induction). e.g.:

Enzyme induction (increase of hepatic metabolism): Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones (e.g. pPhenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John’s wort).

Substances with variable effects on the clearance of Dianette, e.g.:

Also HIV protease (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), and combinations of them, have been reported to potentially affect hepatic metabolism.When co-administered with Diane-35, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of estrogen or progestin. These changes may be clinically relevant in some cases.

Antibiotics (interference with enterohepatic circulation): Some clinical reports suggest that enterohepatic circulation of oestrogens may decrease when certain antibiotic agents are given, which may reduce ethinylestradiol concentrations (e.g. penicillins, tetracyclines).

10. Date of Revision of the Text

September 2013

January 2014

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

4.1 Therapeutic indications

Treatment of moderate to severe acne related to androgen-sensitivity (with or without seborrhoea) and/or hirsutism, in women of reproductive age.

For the treatment of acne, Dianette should only be used after topical therapy or systemic antibiotic treatments have failed.

Since Dianette is also a hormonal contraceptive, it should not be used in combination with other hormonal contraceptives (see section 4.3).

For use in the management of severe acne vulgaris, especially those forms which are accompanied by seborrhoea or by inflammation or formation of nodes (acne papulopustulosa, acne nodulocystica) in women.

Oral contraception for the woman suffering from the above.

Although Dianette also acts as an oral contraceptive, it should not be used in women solely for contraception, but should be reserved for those women requiring treatment for the androgen-dependent acne described.

4.2. Posology and method of administration

DurationLength of use

Time to relieve of symptoms is at least three months. The need to continue treatment should be evaluated periodically by the treating physician.

4.3 Contraindications

Combined oral contraceptives (COCs) should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during COC use, Dianette should be stopped immediately.

·         Concomitant use with another hormonal contraceptive (see section 4.1).

·         Presence or history of venous thrombosis (deep venous thrombosis, pulmonary embolism).

·         Presence or history of arterial thrombosis (e.g. myocardial infarction, cerebrovascular accident) or prodromal conditions (e.g. transient ischaemic attack and, angina pectoris).

·         Presence or history of cerebrovascular accident

·         The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contraindication (see under section 4.4, Special warnings and precautions for use) such as:

o    diabetes mellitus with vascular symptoms

o    severe hypertension

o    severe dyslipoproteinaemia. 

·         Hereditary or acquired Known predisposition for venous or arterial thrombosis, such as antithrombin III deficiency, protein C deficiency, protein S deficiency, Activated Protein C (APC) resistance,(e.g. Factor V Leiden), hyperhomocysteinaemia, and antiphospholipid- antibodies (anticardiolipin-antibodies, lupus anticoagulant).

·         History of migraine with focal neurological symptoms.

·         Diabetes mellitus with vascular involvement.

·         Severe hepatic disease as long as liver function values have not returned to normal.

·         Presence or history of liver tumors (benign or malignant).

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

·         Undiagnosed vaginal bleeding.

·         Known or suspected pregnancy.

·         Lactation.

·         Hypersensitivity to the active substances or to any of the excipients.

·         Porphyria.

·         Uncontrolled hypertension.

Dianette is not for use in men.

4.4 Special warnings and precautions for use

Time to relief of symptoms is at least three months. The need to continue treatment should be evaluated periodically by the treating physician (see section 4.2).

If any of the conditions/risk factors mentioned below is present, the benefits of the use of Dianette should be weighed against the possible risk for each individual woman and discussed with the woman before she decides to start using Dianetteit. 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 use of Dianette should be discontinued.

Circulatory Disorders

The use of Dianette 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 starts Dianette or when restarting or switching after a pill-free interval of at least a month. Venous thromboembolism can be fatal in 1-2% of cases.

Epidemiological studies have shown that the incidence of VTE is 1.5 to 2 times higher in users of Dianette than in users of levonorgestrel-containing combined oral contraceptives (COCs) and may be similar to the risk for desogestrel / gestodene / drospirenone-containing COCs.

The user group of Dianette is likely to include patients that may have an inherently increased cardiovascular risk such as that associated with polycystic ovarian syndrome.

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

Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in hormonal contraceptive users.

Symptoms of venous or arterial thrombosis 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 of venous thromboembolic events increases with:

- increasing age;

- smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age. Women over 35 years of age should be strongly advised not to smoke if they wish to use Dianette);

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

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

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

The risk of arterial thromboembolic complications or of a cerebrovascular accident increases with:

- increasing age;

- smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age. Women over 35 years of age should be strongly advised not to smoke if they wish to use Dianette);

- dyslipoproteinemia;

- obesity (body mass index over 30 kg/m²);

- hypertension;

- migraine;

- valvular heart disease;

- atrial fibrillation;

- a positive family history (arterial thrombosis ever in a sibling or parent at a

relatively early age). If a hereditary predisposition is suspected, the woman

should be referred to a specialist for advice before deciding about any

hormonal contraceptive use.

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

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

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

Women using Dianette should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, Dianette use should be discontinued. Adequate contraception should be initiated because of the teratogenicity of anti-coagulant therapy (coumarins).

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 COC. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 cases per 100,000 pregnancies. VTE is fatal in 1-2% of the cases.

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

There is some epidemiological evidence that the incidence of VTE is higher in users of Dianette when compared to users of COCs with low oestrogen content (<50 mcg). The user group of Dianette as a treatment for severe acne is likely to include patients that may have an inherently increased cardiovascular risk such as that associated with polycystic ovarian syndrome.

The use of COCs in general has been associated with an increased risk of arterial thrombotic/thromboembolic events such as acute myocardial infarction (AMI) or cerebrovascular accident i.e. stroke, a risk that is strongly influenced by the presence of other risk factors (e.g. smoking, high blood pressure and age) (see also below). These events occur rarely. It has not been studied how Dianette modifies the risk of AMI.

The risk of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident increases with:

·         age;

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

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

·         prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilization

·         smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age); if a woman over 35 wishes to use a COC such as Dianette she should be strongly advised to stop smoking.

·         dyslipoproteinemia;

·         hypertension;

·         migraine;

·         valvular heart disease;

·         atrial fibrillation;

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

The increased risk of thromboembolism in the puerperium must be considered (for information on pregnancy and lactation see section 4.6 ‘Pregnancy and lactation’).

4.8 Undesirable effects

There is an increased risk of thromboembolism for all women who use Dianette (see section 4.4).

The most serious undesirable effects associated with the use of COCs are listed in section 4.4, Special warnings and precautions for use.

Other side effects that have been reported in users of Dianette are:

*The most appropriate MedDRA term (version 12.0) to describe a certain adverse reaction is listed.

Synonyms or related conditions are not listed, but should be taken into account as well.

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

·         Venous thromboembolic disorders

·         Arterial thromboembolic disorders

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 preferably through the online reporting option accessible from the IMB homepage. A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’, in addition to the traditional post-paid ‘yellow card’ option.

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

10. Date of Revision of the Text

September August 2013

4.2. Posology and method of administration

How to start Dianette

·         No preceding hormonal contraceptive use (in the past month)

Tablet-taking has to start on day 1 of the woman’s natural cycle (i.e. the first day of her menstrual bleeding). Starting on days 2 - 5 is allowed, but during the first cycle a barrier method is recommended in addition for the first 7 days of tablet-taking.[EP1] 

·         Switching Changing from a combined hormonal contraceptive (combined oral contraceptive/ (COC), vaginal ring or transdermal patch)

The woman should start with Dianette preferably on the day after the last active hormone-containing tablet (the last tablet containing the active substances) of her previous COC, but at the latest on the day following the usual tablet-free or placebohormone-free tablet interval of her previous COC.

If a vaginal ring or transdermal patch has been used, the woman should, preferably, start using Dianette on the day of removal, but at the latest when the next application would have been due.

·         Switching Changing from a progestogen-only-method (progestogen-only minipill, injection, implant) or from a progestogen-releasing intrauterine system (IUS)

The woman may switch any day from the progestogen-only minipill (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due), but should in all of these cases be advised to additionally use a barrier method for the first 7 days of tablet-taking.

Management of missed tablets

If the user is less than 12 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 12 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. Tablet-taking must never be discontinued for longer than 7 days

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

If the woman forgets to take an active Dianette tablet then it must be taken within 12 hours of the usual time for taking it. If a missed tablet is not taken within 12 hours then it should be taken when remembered and the remaining tablets taken as usual with extra non-hormonal contraceptive measures (except rhythm or temperature method) used for the next 7 days. If these seven days extend beyond the end of the pack then the next pack of tablets should be commenced at once with no tablet-free interval. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be excluded before resuming with the next pack.

Accordingly the following advice can be given in daily practice:

·      Week 1

The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. In addition, a barrier method such as a condom should be used for the next 7 days. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered. The more tablets are missed the closer they are to the regular tablet-free interval, the higher the risk of a pregnancy.

·     Week 2

The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. However, if she missed more than 1 tablet, the woman should be advised to use extra precautions for 7 days.

·     Week 3

The risk of reduced reliability is imminent because of the forthcoming tablet-free interval. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has taken all tablets correctly. If this is not the case, the woman should be advised to follow the first two options and to use extra precautions for the next 7 days as well.

1.  The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. The next pack must be started as soon as the current pack is finished, i.e. no gap should be left between packs. The user is unlikely to have a withdrawal bleed until the end of the second pack, but she may experience spotting or breakthrough bleeding on the tablet-taking days.

2.  The woman may also be advised to discontinue tablet-taking from the current pack. She should then have a tablet-free interval of up to 7 days, including the days she missed tablets, and subsequently continue with the next pack.

If the woman missed tablets and subsequently has no withdrawal bleed in the first normal tablet-free interval, the possibility of a pregnancy should be considered.

Advice in case of gastro-intestinal disturbances

In case of severe gastrointestinal 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 tablet-taking, a new (replacement) tablet should be taken as soon as possible. The new tablet should be taken within 12 hours of the usual time of tablet-taking if possible. If more than 12 hours elapse[EP2] ,  the advice concerning missed tablets, as given in section 4.2 4.2, Posology and method of administration’Management of missed pills’ 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. [EP3] 

Tablet-taking from the current pack should be continued. Additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used during the gastro-intestinal upset and for 7 days following the upset. If these 7 days overrun the end of a pack, the next pack should be started without a break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before resuming with the next pack.

If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) needed from another pack. In cases of persisting or recurrent gastrointestinal disturbances additional contraceptive measures should be taken and the physician should be informed.[EP4] 

Length of use

The length of use depends on the severity of the clinical picture. Complete remission of acne is expected within a few months of commencing treatment, but in particularly severe cases treatment for longer may be necessary before the full benefit is seen.

It is recommended that treatment be withdrawn 3 to 4 cycles after the acne has satisfactorily resolved and that Dianette is not continued solely to provide oral contraception. Repeat courses of Dianette may be given if the androgen-dependent acne recurs. In this case, an early restart of Dianette should be considered. In case of a restart of Dianette (following a 4 week or greater pill free interval), the increased risk of VTE should be considered (see section 4.4 Special warnings and precautions for use).

Additional information on special populations

Geriatric patients
Not applicable. Dianette is not indicated after menopause.

Patients with hepatic impairment
Dianette is contraindicated in women with severe hepatic diseases as long as liver function values have not returned to normal. See also section ‘Contraindications’.

Patients with renal impairment
Dianette has not been specifically studied in renally impaired patients. Available data do not suggest a change in treatment in this patient population.

4.3 Contraindications

Combined oral contraceptives (COCs) should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during COC use, Dianette should be stopped immediately.

·         Presence or history of venous thrombosis (deep venous thrombosis, pulmonary embolism).

·            Presence or history of arterial thrombosis (myocardial infarction, cerebrovascular accident) or prodromal conditions (e.g. transient ischaemic attack, angina pectoris).

·            The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contraindication (see under section 4.4, Special warnings and precautions for use). 

·          

·         Known predisposition for venous or arterial thrombosis, such as antithrombin III deficiency, protein C deficiency, protein S deficiency, Activated Protein C (APC) resistance (e.g. Factor V Leiden), hyperhomocysteinaemia, and antiphospholipid antibodies.

·         History of migraine with focal neurological symptoms.

·         Diabetes mellitus with vascular involvement.

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

·         Presence or history of liver tumors (benign or malignant).

·             

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

·         Undiagnosed vaginal bleeding.

·         Known or suspected pregnancy.

·         Lactation.

·         Hypersensitivity to the active substances or to any of the excipients.

·         Porphyria.

·         Uncontrolled hypertension.

Dianette is not for use in men.

4.4 Special warnings and precautions for use

The clinical and epidemiological experience with estrogen/progestogen combinations like Dianette is predominantly based on combined oral contraceptives (COC). Therefore the following warnings related to COC use apply also for Dianette.

Conditions which need supervision

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

·            Risk factors for thrombo-embolic disorders (see above)

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

·            Hypertension

·            Liver disorders (e.g. liver adenoma)

·            Cholelithiasis, jaundice and/or pruritus related to cholestasis

·            Herpes gestationis

·            Migraine or (severe) headache

·            Systemic lupus erythematosus

·            Endogenous depression

·            Asthma

·            Otosclerosis related hearing loss.[EP5] 

The use of COCs in general has been associated with an increased risk of arterial thrombotic/thromboembolic events such as acute myocardial infarction (AMI) or cerebrovascular accident i.e. stroke, a risk that is strongly influenced by the presence of other risk factors (e.g. smoking, high blood pressure and age) (see also below). These events occur rarely. It has not been studied how Dianette modifies the risk of AMI.[EP6] 

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset of venous thrombosis.[EP7] 

Tumors

An increased risk of cervical cancer in long-term users of COCs has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV).[EO8] 

Conditions which need supervision

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

·            Risk factors for thrombo-embolic disorders (see above)

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

·            Hypertension

·            Liver disorders (e.g. liver adenoma)

·            Cholelithiasis, jaundice and/or pruritus related to cholestasis

·            Herpes gestationis

·            Migraine or (severe) headache

·            Systemic lupus erythematosus

·            Endogenous depression

·            Asthma

·            Otosclerosis related hearing loss.[EP9] 

Other conditions

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.

The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: 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.

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice and/or cholestasis related pruritis which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.

Although The use of COCs may have an effect on peripheral insulin resistance and glucose tolerance,, there is no evidence to alter the therapeutic regimen in diabetics using low dose COCs (containing < 0.05 mg ethinylestradiol) . However, diabetic women should be carefully observed while taking COCs.

Worsening of endogenous depression, of epilepsy, of Crohn’s disease and of ulcerative colitis have been associated with COC use.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs.

If in women suffering from hirsutism, symptoms have recently developed or increased substantially, the causes (androgen-producing tumor, adrenal enzyme defect) must be clarified by differential diagnosis.

Each coated tablet of this medicinal product contains sucrose and 31 mg lactose per tablet. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption who are on a lactose-free diet should take the lactose content into account.

Herbal preparations containing St. John’s wort (Hypericum perforatum) should not be used while taking Dianette due to the risk of decreased plasma concentrations and reduced clinical effects of Dianette (see section 4.5, Interaction with other medicinal products and other forms of interaction). [EP10] 

Medical examination/consultation

….. Pregnancy must be ruled out…..

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.

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.

Effects of other medicaments on Dianette

Interactions of other drugs (enzyme inducers, some antibiotics) with estrogen/progestogen combinations like Dianette may lead to breakthrough bleeding and/or contraceptive failure. Interactions between oestrogen-progestogen combinations like Dianette and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Women on treatment with any of these drugs should temporarily use a barrier method in addition to Dianette or choose another method of contraception. With microsomal enzyme-inducing drugs, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation.

Women on treatment with antibiotics (except rifampicin and griseofulvin) should use the barrier method until 7 days after discontinuation. If the period during which the barrier method is used runs beyond the end of the tablets in the Dianette pack, the next pack should be started without the usual tablet-free interval.

Substances diminishing the efficacy of Dianette (enzyme-inducers and antibiotics)

Enzyme induction (increase of hepatic metabolism): The following interactions have been reported in the literature.

Hepatic metabolism: Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John’s wort).

Also HIV protease (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), and combinations of them, have been reported to potentially affect hepatic metabolism.

Antibiotics (iInterference with eEnterohepatic cCirculation): Some clinical reports suggest that enterohepatic circulation of oestrogens may decrease when certain antibiotic agents are given, which may reduce ethinylestradiol concentrations (e.g. penicillins, tetracyclines).

Women on treatment with any of these drugs should temporarily use a barrier method in addition to Dianette or choose another method of contraception. With microsomal enzyme-inducing drugs, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation. Women on treatment with antibiotics (except rifampicin and griseofulvin) should use the barrier method until 7 days after discontinuation. If the period during which the barrier method is used runs beyond the end of the tablets in the Dianette pack, the next pack should be started without the usual tablet-free interval.

Effects of estrogen/progestogen combinations on other medicaments

Oral contraceptives may interfere with the metabolism of certain other drugs. Increased plasma concentrations of cyclosporin have been reported with concomitant administration of OCs. COCs have been shown to induce metabolism of lamotrigine resulting in sub-therapeutic plasma concentrations of lamotrigine. Oestrogen/progestogen combinations like Dianette may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).

Other forms of interactions

Laboratory tests

The use of preparations like Dianette 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.

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

4.6 Fertility, pregnancy and lactation

Animal studies have revealed that feminization of male fetuses may occur if cyproterone acetate is administered during the phase of embryogenesis at which differentiation of the external genitalia occurs. Although the results of these tests are not necessarily relevant to man, Tthe possibility must be considered that administration of Dianette to women after the 45^th day of pregnancy could cause feminization of male fetuses.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. No effects on ability to drive and use machines have been observed in users of Dianette.

Not applicable

4.8 Undesirable effects

Side effects that have been reported in users of COCs but for which the association has been neither confirmed nor refuted are:

The most serious undesirable effects associated with the use of COCs are listed in section 4.4, Special warnings and precautions for use.

Other side effects that have been reported in users of Dianette but for which the association has been neither confirmed nor refuted are:

Table of side effects is here

Under the table, the following has been inserted:

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. For further information, see sections ‘Contraindications’ and ‘Special warnings and precautions for use’.

7. Marketing Authorisation Holder

Bayer Limited

The Atrium

Blackthorn Road

Dublin 18

Ireland

10. Date of Revision of the Text

August 2013 To be inserted on Approval.

• In Section 4.3 (Contraindications), deletion of Pancreatitis as a contraindication.
• In Sections 4.6, 6.1 and 6.6 : Minor editorial changes, update to title headings.
• In Section 10 ( Date of Revison of Text ) updated to August 2011 from January 2009.

Update of SPC following renewal 2008

Main Changes to the SPC

Section 4.2 Posology and Method of Administration

Heading, How to take Dianette:

Addition of the following information: Dianette is to be taken regularly in order to achieve the therapeutic efficacy and the required contraceptive protection. Combined oral contraceptives when taken correctly have a failure rate of approximately 1% per year.

Heading, How to start Dianette:

Addition of information on switching to Dianette from a vaginal ring or transdermal patch.

Section 4.4 Special warnings and precautions for use

Addition of the following warning:

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

Section 4.5 Interaction with other medicaments and other forms of interaction

Addition of information regarding possible interaction with HIV protease and non-nucleoside reverse transcriptase inhibitors.

Additional information regarding the effect of Dianette on the metabolism of other drugs: Concomitant use of Dianette may increase cyclosporin levels and decrease lamotrigine levels.

Section 4.8 Undesirable Effects

Addition of the following information:

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

Main Changes to the SPC include:

Section 4.2 Posology and method of administration

Change to layout. Text is arranged under the following headings:

-         How to take Dianette

-         How to start Dianette

-         Management of missed tablets

-         Advice in case of gastro-intestinal disturbances

-         Length of use

Section 4.3 Contraindications

Update of contraindications in line with the most recent safety information.

Addition of the following contra-indications:

-         Presence or history of prodromal conditions of arterial thrombosis

-         Known predisposition for venous or arterial thrombosis, such as antithrombin III deficiency, protein C deficiency, protein S deficiency, Activated Protein C (APC) resistance (e.g. Factor V Leiden), hyperhomocysteinaemia, and antiphospholipid antibodies

-         History of migraine with focal neurological symptoms

-         Pancreatitis or a history thereof if associated with severe hypertriglyceridemia

-         Presence or history of liver tumors (benign or malignant)

-         Known or suspected pregnancy

-         Lactation

-         Porphyria

-         Uncontrolled hypertension

Deletion of the following contra-indications:

-         Sickle-cell anaemia

-         Pemphigoid gestationis

-         Deterioration of otosclerosis during pregnancy

Section 4.4 Special warnings and precautions for use

Revised/additional text regarding:

-         conditions which require supervision during use of Dianette

-         risk factors for arterial thrombotic / thromboembolic events

-         use in women with hypertriglyceridemia or family history thereof

-         hypertension

-         conditions reported to occur during both pregnancy and COC use

-         peripheral insulin resistance and glucose tolerance

-         risk of chloasma, Crohn’s disease and ulcerative colitis

-         risk of breast and cervical cancer

-         reduced cycle control

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

Revised/additional text:

- interaction with drugs which induce hepatic metabolism

Section 4.6 Pregnancy and lactation

Use during pregnancy:

Inclusion of data from animal reproduction-toxicological studies.

Undesirable effects have been tabulated according to the System Organ Class affected and the frequency of occurrence.

In addition, the following possible undesirable effects have been included: breast pain, abdominal pain, breast hypertrophy, migraine, vaginal discharge, breast discharge, hypersensitivity,

Section 5.1 Pharmacodynamic properties

Revised/additional information regarding the mechanism(s) of action of the active substances.

Section 5.2 Pharmacokinetic properties

Details of the Absorption, Distribution, Metabolism, Elimination and Steady-state conditions of each of the active substances are described.

Section 5.3 Preclinical Safety Data

Updated in line with the most recently available information