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 SeptemberMay2022

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

SeptemberMay2022

Due to harmonization of the label of the company’s HRT products it is proposed to include the following harmonized EU text under Section 3 of the PIL (deleted text in strikethrough and new text in bold underlined):

Product Information Leaflet Section 3.

“How to take Angeliq

[…]

If you take more Angeliq than you should

Overdose may cause nausea If you have taken too many Angeliq tablets by mistake, you may feel sick, and vomiting or have some menstruation-likeand irregular bleeding. No specific treatment is necessary but you should consult your doctor or pharmacistif you are worriedconcerned.

[…]”

6.    Contents of the pack and other information

[…]

This leaflet was last approved in February 2022May2022.

Section 4.2 Posology and method of administration

“4.2 Posology and method of administration

[…]

Geriatric patients

There are no data suggesting a need for dosage adjustment in elderly patients. In women aged 65 years or older, see section 4.4.”

“Patients with hepatic impairment

In women with mild or moderate hepatic impairment, drospirenone is well tolerated (see section 5.2. Pharmacokinetic properties). Angeliq is contraindicated in women with severe hepatic disease (see section 4.3). For women with impaired liver function, close supervision is needed and in case of deterioration of markers of liver function, use of HRT should be stopped (see section 4.4).”

SmPC Section 4.9 Overdose

“4.9 Overdose

[…]

4.9 Overdose

In clinical studies in male volunteers doses up to 100 mg of drospirenone were well tolerated. Based on general experience with combined oral contraceptives, symptoms that may possibly occur are Overdose may cause nausea and vomiting and – in young girls and some women – vaginalwithdrawal bleeding may occur in some women. There are no specific antidotes, and, therefore, treatment should be symptomatic.

[…]”

10. DATE OF REVISION OF THE TEXT

February 2022May 2022

Reason for change:

In the framework of the PSUSA on estradiol / nomegestrol acetate, PRAC considered that the risk of angioedema in women with inherited or acquired types and drug-drug interaction with hepatitis C virus (HCV) treatments would also be relevant to be included in the product information of estradiol- containing products (as single agent or fixed dose combinations). Therefore, affected MAHs of estradiol-containing products need to consider implementing the same wording as agreed in the PSUSA on estradiol / nomegestrol acetate in their product information regarding both the angioedema risk and drug-drug interaction with HCV treatments.

Based on this, CMDh agreed an update of its Core SmPC and PL (and annexes) for Hormone Replacement Therapy (HRT) products in line with the conclusion of the above-mentioned PSUSA and following publication of the EC decision on the PSUSA on estradol / nomegesterol acetate, a variation to implement the recommendations for the update of the product information was submitted and the following sections of the PIL for Angeliq were subsequently updated:

2.   What you need to know before you take Angeliq

[…]

Warnings and precautions

Talk to your doctor or pharmacist before taking Angeliq. Tell your doctor if you have ever had any of the following problems, before you start treatment, as these may return or become worse during treatment with Angeliq. If so, you should see your doctor more often for check-ups:

• fibroids inside your womb
• growth of womb lining outside your womb (endometriosis) or a history of excessive growth of the womb lining (endometrial hyperplasia)
• increased risk  of developing blood clots (see “Blood clots in a vein (thrombosis)”)
• increased risk of getting an oestrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer)
• high blood pressure
• a liver disorder such as benign liver tumour
• diabetes
• gallstones
• migraine or severe headaches
• a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE)
• epilepsy
• asthma
• a disease affecting the eardrum and hearing (otosclerosis)
• a very high level of fat in your blood (triglycerides)
• fluid retention due to cardiac or kidney problems
• hereditary and acquired angioedema

Stop taking Angeliq and see a doctor immediately

If you notice any of the following when taking HRT:

• • any of the conditions mentioned in the ‘DO NOT take Angeliq’ section
  • yellowing of your skin or the whites of your eyes (jaundice). These may be signs of a liver disease
  • swollen face, tongue and/or throat and/or difficulty swallowing or hives, together with difficulty breathing which are suggestive of angioedema
  • a large rise in your blood pressure (symptoms may be headache, tiredness, dizziness)
  • migraine-like headaches which happen for the first time
  • if you become pregnant
  • if you notice signs of a blood clot, such as
    • painful swelling and redness of the legs
    • sudden chest pain
    • difficulty breathing

For more information see “Blood clots in a vein (thrombosis)”

[…]

Other medicines and Angeliq

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Some medicines may interfere with the effect of Angeliq. This might lead to irregular bleeding.

This applies to the following medicines:

• medicines for epilepsy (such as barbiturates, phenytoin, primidone, carbamazepine, oxcarbazepine, topiramate and felbamate)
• medicines for tuberculosis (such as rifamipicin and rifabutin)
• medicines for HIV and Hepatitis C virus infections (so-called protease inhibitors and non-nucleoside reverse transcriptase inhibitors such as nevirapine, efavirenz, nelfinavir and ritonavir)

• the herbal remedy St. John’s wort (Hypericum perforatum)
• medicines for Hepatitis C virus (HCV) (such as combination regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir as well as a regimen with glecaprevir/pibrentasvir) may cause increases in liver function blood test results (increase in ALT liver enzyme) in women using CHCs containing ethinylestradiol. Angeliq contains estradiol instead of ethinylestradiol. It is not known whether an increase in ALT liver enzyme can occur when using Angeliq with this HCV combination regimen. Your doctor will advise you.
• medicines for treatment of fungal infections (such as griseofulvin, itraconazole, ketoconazole, voriconazole, fluconazole)
• medicines for treatment of bacterial infections  (such as clarithromycin, erythromycin)
• medicines for treatment of certain heart diseases, high blood pressure (such as verapamil, diltiazem)
• grapefruit juice

[…]

Marketing Authorisation Holder

Bayer Limited

The Atrium

Blackthorn Road

Dublin 18, Ireland

Manufacturer

Bayer AG

Müllerstrasse 170 – 178

D-13353 Berlin

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

Angeliq – Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Germany, Greece, Finland, France, Ireland, Italy, Lithuania, Latvia, Luxembourg, Malta, Netherlands, Poland, Portugal, Slovenia, Slovakia, Spain,

Angemin – Denmark, Iceland, Sweden

This leaflet was last approved in February 2022September 2020.

Reason for change:

In the framework of the PSUSA on estradiol / nomegestrol acetate, PRAC considered that the risk of angioedema in women with inherited or acquired types and drug-drug interaction with hepatitis C virus (HCV) treatments would also be relevant to be included in the product information of estradiol- containing products (as single agent or fixed dose combinations). Therefore, affected MAHs of estradiol-containing products need to consider implementing the same wording as agreed in the PSUSA on estradiol / nomegestrol acetate in their product information regarding both the angioedema risk and drug-drug interaction with HCV treatments.

Based on this, CMDh agreed an update of its Core SmPC and PL (and annexes) for Hormone Replacement Therapy (HRT) products in line with the conclusion of the above-mentioned PSUSA and following publication of the EC decision on the PSUSA on estradol / nomegesterol acetate, a variation to implement the recommendations for the update of the product information was submitted and the following sections of the SmPC for Angeliq were subsequently updated:

4.4     Special warnings and precautions for use

[…]

Hepatitis C

During clinical trials with the hepatitis C virus (HCV) combination regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen glecaprevir/pibrentasvir. See section 4.5.

Other conditions

Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.

Women with pre-existing hypertriglyceridemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

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

4.5     Interaction with other medicinal products and other forms of interaction

[…]

Other forms of interactions

During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen with glecaprevir/pibrentasvir (see section 4.4).

10. DATE OF REVISION OF THE TEXT

September 2020February 2022

In the framework of the PSUSA on estradiol / nomegestrol acetate, PRAC considered that the risk of angioedema in women with inherited or acquired types and drug-drug interaction with hepatitis C virus (HCV) treatments would also be relevant to be included in the product information of estradiol- containing products (as single agent or fixed dose combinations). Therefore, affected MAHs of estradiol-containing products need to consider implementing the same wording as agreed in the PSUSA on estradiol / nomegestrol acetate in their product information regarding both the angioedema risk and drug-drug interaction with HCV treatments.

In the framework of the PSUSA on estradiol / nomegestrol acetate, PRAC considered that the risk of angioedema in women with inherited or acquired types and drug-drug interaction with hepatitis C virus (HCV) treatments would also be relevant to be included in the product information of estradiol- containing products (as single agent or fixed dose combinations)

Reason for change:

• To implement the outcome of the PRAC signal assessment on new information on the known risk of breast cancer with hormone replacement therapy (HRT) products (EPITT 19482) the PRAC recommendation was published on 23 June 2020.
• To adjust the Lactose warning in Section 4.4 in accordance to the Annex to the European Commission guideline on “Excipients in the labelling and package leaflet of medicinal products for human use”. The excipient warning was slightly updated with revision 1 (22 November 2019, EMA/CHMP/302620/2017 Rev. 1).
• Update the reporting of side effects details for the HPRA in section 4.

4.4 Special warnings and precautions for use

[…]

Breast cancer

The overall evidence suggestsshows an increased risk of breast cancer in women taking combined oestrogen-progestagen and possibly alsoor oestrogen-only HRT, that is dependent on the duration of taking HRT.

Combined oestrogen-progestagen therapy

The randomised placebo-controlled trial, the Women’s Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestagen for HRT that becomes apparent after about 3 (1-4) years (see section 4.8).

Estrogen-only therapy

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of estrogen-progestogen combinations (see section 4.8).

The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) yearsResults from a large meta-analysis showed that after stopping treatment., the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.

[…]

Other conditions

[…]

Each tablet of this medicinal product contains 46 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp total lactase deficiency or glucose-galactose malabsorption who are on a lactose free diet should not take this medicine.amount into consideration.

[…]

4.8 Undesirable effects

[…]

Breast cancer risk

• An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years.
• TheAny increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestagen combinations.
• The level of risk is dependent on the duration of use (see section 4.4).
• Absolute risk estimations based on rResults of the largest randomised placebo-controlled trial (WHI study) and the largest meta-analysis of prospective epidemiological studiesy (MWS) are presented.

[…]

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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

October 2016September 2020

Reason for change:

• To implement the outcome of the PRAC signal assessment on new information on the known risk of breast cancer with hormone replacement therapy (HRT) products (EPITT 19482). The PRAC recommendation was published on 23 June 2020.
• To adjust the Lactose warning in Section 2 in accordance to the Annex to the European Commission guideline on “Excipients in the labelling and package leaflet of medicinal products for human use”. The excipient warning was slightly updated with revision 1 (22 November 2019, EMA/CHMP/302620/2017 Rev. 1).
• Deletion of the United Kingdom as member state.
• Update the reporting of side effects details for the HPRA in section 4.
• Addition of the reporting of side effect details for Malta in section 4.

2. What you need to know before you take Angeliq

[….]

Stop taking Angeliq and see a doctor immediately

If you notice any of the following when taking HRT:

• any of the conditions mentioned in the ‘DO NOTDo not take Angeliq section’

 […]

Breast cancer

Evidence suggestsshows that taking combined oestrogen-progestogen and possibly alsoor oestrogen-only hormone replacement therapy (HRT) increases the risk of breast cancer. This extra risk depends on how long you takeuse HRT. The additional risk becomes clear within a few3 years of use.However, it returns to normal within a few years (at most 5) after stopping treatment. After stopping HRT the extra risk will decrease with time, but the risk may persist for 10 years or more if you have used HRT for more than 5 years.

Compare

In women aged 50 to 7954 who are not taking HRT, on average, 913 to 17 in 1000 will be diagnosed with breast cancer over a 5-year period.

For women aged 50 who start taking oestrogen-only HRT for 5 years, there will be 16-17 cases in 1000 users (i.e. an extra 0 to 3 cases).

For women aged 50 to 79 who arestart taking oestrogen-progestogen HRT overfor 5 years, there will be 2113 to 23 cases in 1000 users (i.e. an extra 4 to 86 cases).

Women aged 50 to 59 who are not taking HRT, on average, 27 in 1000 will be diagnosed with breast cancer over a 10-year period.

For women aged 50 who start taking oestrogen-only HRT for 10 years, there will be 34 cases in 1000 users (i.e. an extra 7 cases)

For women aged 50 who start taking oestrogen-progestogen HRT for 10 years, there will be 48 cases in 1000 users (i.e. an extra 21 cases).

[….]

Other medicines and Angeliq

[…]

• medicines for HIV and Hepatitis C vVirus infections (so-called protease inhibitors and non-nucleoside reverse transcriptase inhibitors such as nevirapine, efavirenz, nelfinavir and ritonavir)

[…]

Angeliq contains lactose

Angeliq contains lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, check with contact your doctor before taking this medicinal productAngeliq.

[…]

4. Possible side effects

[….]

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

You can also report side effects directly (see details below). via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. By reporting side effects you can help provide more information on the safety of this medicine.

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

[….]

6. Contents of the pack and other information

[….]

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

Angeliq – Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Germany, Greece, Finland, France, Ireland, Italy, Lithuania, Latvia, Luxembourg, Malta, Netherlands, Poland, Portugal, Slovenia, Slovakia, Spain, United Kingdom

Angemin – Denmark, Iceland, Sweden

This leaflet was last approved in April 2017September 2020.

Deleted     Inserted text

4.4 Special warnings and precautions for use

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies including the WHI trial suggest that the long-term use of combined HRT may confer a similar, or slightly smaller risk.

Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.

Some other studies, including the WHI trial, suggest that use of combined HRTs may be associated with a similar or slightly smaller risk (see section 4.8).

[…]

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 medicinal products on Angeliq

Substances increasing the clearance of HRTssex hormones (diminished efficacy of HRTs by enzyme-induction):

The metabolism of oestrogens (and progestogens) may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital,barbiturates, phenytoin, primidone, carbamaezaepine,) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz) and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John's Wort (hypericum perforatum).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Oxcarbazepine, topiramte, felbamate, griseofulvin and Hherbal preparations containing St. John’s wort (Hypericum perforatum) may induce the metabolism of oestrogens (and progestogens).

Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.

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.

Substances with variable effects on the clearance of HRTssex hormones:

When co-administered with HRTssex hormones, many combinations of  HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of oestrogen or progestins or both. The net effect of theseThese 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.

Substances decreasing the clearance of HRTs–sex hormones (enzyme inhibitors)

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the progestin or the oestrogen or both.

In a multiple dose study with a drospirenone (3 mg/day) / oestradiol (1.5 mg/day) combination, co-administration of the strong CYP3A4 inhibitor ketoconazole for 10 days increased the AUC(0 24h) of drospirenone 2.30 fold (90%CI: 2.08, 2.54). No change was observed for oestradiol, although the AUC(0 24h) of its less potent metabolite oestrone increased 1.39-fold (90%CI: 1.27, 1.52).

[…]

Other forms of interaction

Laboratory tests

The use of sex 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. sex hormone binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the reference normal laboratory range. Glucose tolerance was not compromised by the use of Angeliq. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity.

Ovarian cancer

Long term use Use of oestrogen-only and or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Section 4.4). In the million Women Study 5 years of HRT resulted in 1 extra case per 2500 users.

A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.

10. DATE OF REVISION OF THE TEXT

May 2015October 2016

Angeliq – PA 1410/13/1
14044
BEC 6082
www.medicines.ie

(Inserted Text; Deleted Text)

2.            QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipient with known effect: 46 mg lactose

For a the full list of excipients, see section 6.1

4.2          Posology and method of administration

Dosage Posology

Method of Aadministration

Additional information on special populations

Children and adolescents Paediatric population

4.3       Contraindications

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

4.5       Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on Angeliq

Substances increasing the clearance of HRTs (diminished efficacy of HRTs by enzyme-induction)

…..

Substances with variable effects on the clearance of HRTs:

When co-administered with HRTs, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of oestrogen or progestin or both. These changes may be clinically relevant in some cases.

Substances decreasing the clearance of HRTs (enzyme inhibitors)

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the progestin or the oestrogen or both. In a multiple dose study with a drospirenone (3mg/day) / oestradiol (1.5mg/day) combination, co-administration of the strong CYP3A4 inhibitor ketoconazole for 10 days increased the AUC(0 24h) of drospirenone 2.30 fold (90%CI: 2.08, 2.54). No change was observed for oestradiol, although the AUC (0 24h) of its less potent metabolite oestrone increased 1.39-fold (90%CI: 1.27, 1.52).
The main metabolites of drospirenone are generated without involvement of the cytochrome p450 system. Inhibitors of this enzyme system are therefore unlikely to influence the metabolism of drospirenone.

Interaction Effect of Angeliq with on other medicinal products

In vitro, drospirenone is capable to inhibit weakly to moderately the cytochrome p450 enzymes CYP1A1, CYP2C9, CYP2C19 and CYP3A4.

Based on in vitro inhibition studies and on in vivo interaction studies in female volunteers receiving steady state doses of 3 mg drospirenone per day and using omeprazole, simvastatin, or midazolam as marker substrate, a clinically relevant interaction of drospirenone at doses of 3 mg with the cytochrome P450 enzyme mediated metabolism of other drugs is unlikely.

4.6          Fertility, Pregnancy pregnancy and lactation

…

Lactation Breastfeeding

4.7          Effects on ability to drive and use machines

No effects on the ability to drive or use machines have been observed.

Angeliq has no influence on the ability to drive and use machines.

4.8          Undesirable effects

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 the national reporting system listed in Appendix V HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

5.2          Pharmacokinetic properties

Drospirenone

·         Metabolism 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-sulphate, formed by reduction and subsequent sulfatation both of which are formed without involvement of the P450 system. Both major metabolites are pharmacologically inactive. Drospirenone is also subject to oxidative metabolism catalysed by metabolized to a minor extent by cytochrome P450 CYP3A4 based on in vitro data. In vitro and clinical studies do not indicate an inhibitory effects on DRSP on CYP enzymes after administration of Angeliq.

Oestradiol

·         Metabolism Biotransformation

…

·         Steady-state conditions and linearity

6.5          Nature and contents of container

....

Not all pack sizes may be marketed.

Each tablet of this medicinal product contains 46 mg lactose per tablet. 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.

Main Changes to the SPC

Section 4.4 Special warnings and precautions for use

Updated information provided regarding monitoring of patients with renal insufficiency (especially during the concomitant use of potassium-sparing medications).

Addition of information regarding possible decreases in blood pressure when used in hypertensive women. (Angeliq should not be used to treat hypertension.)

Section 4.5 Interaction with other medicaments and other forms of interaction

Additional information:

• Results of drug-drug interaction studies using drospirenone and simvastatin.
• Hypertensive women treated with Angeliq and antihypertensive medications may experience an additional decrease in blood pressure.

Updated information regarding the concomitant use of Angeliq and NSAIDs or ACE inhibitors / angiotensin II receptor antagonists.

Section 4.8 Undesirable Effects

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

Updated information regarding the most commonly reported adverse reactions; breast pain, bleeding irregularities and spotting.

Additional possible undesirable effects have been included in the following classes:

Metabolism and nutrition, psychiatric, eye, ear and labyrinth, vascular, gastrointestinal, hepatobiliary, skin and subcutaneous tissue, musculoskeletal and connective tissue, renal and urinary, reproductive system and breast disorders and general disorders and administration site conditions.

Inclusion of additional information regarding use in special populations (hypertensive women).

Inclusion of information regarding other undesirable effects reported in association with HRT products.

Section 5.1 Pharmacodynamic Properties

Inclusion of clinical trial information regarding the anti-mineralocorticoid activity of drospirenone.