4.1. Therapeutic indications

Hormone replacement therapy for oestrogen deficiency symptoms in postmenopausal women more than 1 year post menopause.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.

(See also section 4.4)

The experience treating women older than 65 years is limited.

4.2. Posology and method of administration

Women who do not take hormone replacement therapy (HRT) or women who change from another continuous combined product may start treatment at any time. Women changing from a cyclic, sequential combined HRT regimen, treatment should begin the day following completion of the prior regimen.

Posology

One tablet is taken daily. Each blister is for 28 days of treatment.

Method of administration

The tablets are to be swallowed whole with some liquid irrespective of food intake. Treatment is continuous, which means that the next pack follows immediately without a break. The tablets should preferably be taken at the same time every day. If a tablet is forgotten it should be taken as soon as possible. If more than 24 hours have elapsed no extra tablet needs to be taken. If several tablets are forgotten, vaginal bleeding may occur.

For treatment of post menopausal symptoms, the lowest effective dose should be used.

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used.

Additional information on special populations

Paediatric population

Angeliq is not indicated for use in children and adolescents.

Geriatric patients

There are no data suggesting a need for dosage adjustment in elderly patients.

Patients with hepatic impairment

In women with mild or moderate hepatic impairment, drospirenone is well tolerated (see section 5.2.). 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).

Patients with renal impairment

In women with mild or moderate renal impairment, a slight increase of drospirenone exposure was observed but is not expected to be of clinical relevance (see section 5.2). Angeliq is contraindicated in women with severe renal disease (see section 4.3).

4.3. Contraindications

• Undiagnosed genital bleeding

• Known, past or suspected cancer of the breast

• Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer)

• Untreated endometrial hyperplasia

• Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)

• Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)

• Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal

• Known thrombophilic disorders (e.g. protein C protein S, or antithrombin deficiency, see section 4.4

• Severe renal insufficiency or acute renal failure

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

• Porphyria

4.4. Special warnings and precautions for use

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

Medical examination/follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse. Investigations, including appropriate imaging tools, e.g mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

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

• Leiomyoma (uterine fibroids) or endometriosis,

• Risk factors for, thromboembolic disorders (see below)

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

• Hypertension

• Liver disorders (e.g. liver adenoma)

• Diabetes mellitus with or without vascular involvement

• Cholelithiasis

• Migraine or (severe) headache

• Systemic lupus erythematosus

• A history of endometrial hyperplasia (see below)

• Epilepsy

• Asthma

• Otosclerosis

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in case a contra-indication is discovered and in the following situations:

• Jaundice or deterioration in liver function

• Significant increase in blood pressure

• New onset of migraine-type headache

• Pregnancy

Endometrial hyperplasia and carcinoma

In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.

The addition of a progestogen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.

Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Breast cancer

The overall evidence shows an increased risk of breast cancer in women taking combined oestrogen-progestogen or 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-progestogen 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 lower than that found in users of estrogen-progestogen combinations (see section 4.8).

Results 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.

HRT, especially oestrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer.

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).

Venous thromboembolism

HRT is associated with a 1.3- to 3-fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (see section 4.8).

Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, a personal history or family history obesity (BMI > 30 kg/m2) pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE.

Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see Section 4.3).

As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestogen or oestrogen-only HRT.

The relative risk of CAD during use of combined oestrogen-progestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen-progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.

Ischaemic stroke

Combined oestrogen-progestogen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see Section 4.8).

Hepatitis C

During clinical trials with the hepatitis C virus (HCV) combination regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin, 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 or sofosbuvir/velpatasvir/voxilaprevir, 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, and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin 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 following combination drug regimens ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofobuvir/velpatasvir/voxilaprevir. 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.

Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.

The progestin component in Angeliq is an aldosterone antagonist exhibiting weak potassium sparing properties. In most cases, no increase of serum potassium levels is to be expected. In a clinical study, however, in some patients with mild or moderate renal impairment and concomitant use of potassium-sparing medicinal products (such as ACE inhibitors, angiotensin II receptor antagonists or NSAIDs) serum potassium levels slightly, but not significantly increased during drospirenone intake. Therefore, it is recommended to check serum potassium during the first month of treatment in patients presenting with renal insufficiency and pretreatment serum potassium in the upper reference range, and particularly during concomitant use of potassium sparing medicinal products (see also section 4.5).

Women with elevated blood pressure may experience a decrease in blood pressure under treatment with Angeliq due to the aldosterone antagonist activity of drospirenone (see section 5.1). Angeliq should not be used to treat hypertension. Women with hypertension should be treated according to hypertension guidelines.

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 HRT.

Each tablet of this medicinal product contains 46 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 sex hormones (diminished efficacy 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. barbiturates, phenytoin, primidone, carbamazepine) 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).

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 sex hormones:

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

Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations.

Substances decreasing the clearance of sex hormones (enzyme inhibitors)

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole), 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) / estradiol (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 estradiol, although the AUC(0 24h) of its less potent metabolite oestrone increased 1.39-fold (90%CI: 1.27, 1.52).

Effect of Angeliq 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 vivo interaction studies in female volunteers 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.

Concomitant use of Angeliq and either NSAIDs or ACE inhibitors / angiotensin II receptor antagonists is unlikely to increase serum potassium. However, concomitant use of all these three types of medications together may cause a small increase in serum potassium, which is more pronounced in diabetic women.

Hypertensive women treated with Angeliq and antihypertensive medications may experience an additional decrease in blood pressure (see section 4.4).

Effect of HRT with oestrogens on other medicinal products

Hormone contraceptives containing oestrogens have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both medicinal products together.

Other interactions

Direct acting antiviral agents (DAAs) and ethinylestradiol-containing medicinal products such as CHCs

During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, 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 or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs.

Direct acting antiviral agents (DAAs) and medicinal products containing oestrogens other than ethinylestradiol, such as estradiol

Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin 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 following combination drug regimens: ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section 4.4).

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 normal laboratory range. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity.

4.6. Fertility, pregnancy and lactation

Pregnancy

Angeliq is not indicated during pregnancy. If pregnancy occurs during medication with Angeliq, treatment should be discontinued promptly. No clinical data on exposed pregnancies are available for drospirenone. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of oestrogens with other progestogens have not indicated a teratogenic or foetotoxic effect.

Breastfeeding

Angeliq is not indicated during lactation.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data. The adverse reactions were recorded in 7 Phase III clinical studies (n=2424 women) and considered as at least possibly causally related to Angeliq (E2 1 mg / DRSP doses 0.5, 1, 2, or 3 mg).

The most commonly reported adverse reactions were breast pain (> 10%) and during the first few months of treatment, bleeding and spotting (> 10%). Bleeding irregularities usually subside during continued treatment (see section 5.1). The frequency of bleeding decreases with the duration of treatment.

System Organ Class

Common (≥ 1/100 to < 1/10)

Uncommon(≥ 1/1000 to < 1/100)

Rare(< 1/1000)

Blood and lymphatic system disorders

Anemia

Metabolism and nutrition disorders

Weight increase or weight decrease, anorexia, increased appetite, hyperlipemia

Psychiatric disorders

Depression, emotional lability, nervousness

Sleep disorder, anxiety, libido decreased

Nervous system disorders

Headache

Paresthesia, concentration ability impaired, dizziness

Vertigo

Eye disorders

Eye disorder, visual disturbance

Ear and labyrinth disorders

Tinnitus

Cardiac disorders

Palpitation

Vascular disorders

Embolism, venous thrombosis, hypertension, migraine, thrombophlebitis, varicose veins

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Gastrointestinal disorders

Abdominal pain, nausea, abdomen enlarged

Gastrointestinal disorder, diarrhea, constipation, vomiting, dry mouth, flatulence, taste disturbance

Hepatobiliary disorders

Liver function test abnormal

Cholelithiasis

Skin and subcutaneous tissue disorders

Skin disorder, acne, alopecia, pruritus, rash, hirsutism, hair disorder

Musculoskeletal and connective tissue disorders

Pain in extremity, back pain, arthralgia, muscle cramps

Myalgia

Renal and urinary disorders

Urinary tract disorder, urinary tract infection

Reproductive system and breast disorders

Benign breast neoplasm, breast enlargement, uterine fibroids enlarged, benign neoplasm of cervix uteri, menstrual disorder, vaginal discharge

Breast carcinoma, endometrial hyperplasia, benign uterine neoplasm, fibrocystic breast, uterine disorder, ovarian disorder, cervix disorder, pelvic pain, vulvovaginal disorder, vaginal candidiasis, vaginitis, vaginal dryness

Salpingitis, galactorrhoea

General disorders and administration site conditions

Asthenia, localized oedema

Generalized oedema, chest pain, malaise, sweating increased

Chills

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

Additional information on special populations

The following, undesirable effects classified as at least possibly related to Angeliq treatment by the investigator, were recorded in 2 clinical studies in hypertensive women.

Metabolism and nutrition disorders

Hyperkalemia

Cardiac disorders

Cardiac failure, atrial flutter, QT interval prolonged, cardiomegaly

Investigations

Blood aldosterone increased.

The following undesirable effects have been reported in association with HRT products: Erythema nodosum, eythema multiforme, chloasma and hemorrhagic dermatitis.

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.

• The increased risk in users of oestrogen-only therapy is 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 results of the largest randomised placebo-controlled trial (WHI study) and the largest meta-analysis of prospective epidemiological studies are presented.

Largest meta-analysis of prospective epidemiological Studies

Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m2)

Age at start HRT(years)

Incidence per 1000 never-users of HRT over a 5-year period (50-54 years)a

Risk ratio

Additional cases per 1000 HRT users after 5 years

Oestrogen-only HRT

50

–13.3

1.2

2.7

Combined oestrogen-progestagen

50

–13.3

1.6

8.0

a Taken from baseline incidence rates in England in 2015 in women with BMI 27(kg/m2)

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

Estimated additional risk of breast cancer after 10 years' use in women with BMI 27 (kg/m2)

Age at start HRT

(years)

Incidence per 1000 never-users of HRT over a 10 year period (50-59 years) *

Risk ratio

Additional cases per 1000 HRT users after 10 years

Estrogen only HRT

50

26.6

1.3

7.1

Combined estrogen-progestogen

50

26.6

1.8

20.8

*Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2)

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

US WHI studies - additional risk of breast cancer after 5 years of use

Age range

(years)

Incidence per 1000 women in placebo arm over 5 years

Risk ratio & 95% CI

Additional cases per 1000 HRT users over 5 years (95% CI)

CEE oestrogen-only

50 - 79

21

0.8 (0.7 - 1.0)

-4 (-6 - 0) a

CEE + MPA oestrogen & progestagen b

50 - 79

17

1.2 (1.0 - 1.5)

+4 (0 - 9)

a WHI study in women with no uterus, which did not show an increased in risk of breast cancer.

b When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

Endometrial cancer risk

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with an uterus not using HRT. In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4). Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.

Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer

Use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Section 4.4).

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.

Risk of venous thromboembolism

HRT is associated with a 1.3 - 3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT (see section 4.4). Results of the WHI studies are presented:

WHI Studies - additional risk of VTE over 5 years of use

Age range

(years)

Incidence per 1000 women in placebo arm over 5 years

Risk ratio & 95% CI

Additional cases per 1000 HRT users

Oral oestrogen-only a

50 - 59

7

1.2 (0.6 - 2.4)

1 (-3 - 10)

Oral combined oestrogen-progestagen

50 - 59

4

2.3 (1.2 - 4.3)

5 (1 - 13)

a Study in women with no uterus.

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

The use of oestrogen-only and oestrogen-progestagen therapy is associated with an up to 1.5-fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.

This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4.

WHI studies combined - additional risk of ischaemic stroke a over 5 years of use

Age range

(years)

Incidence per 1000 women in placebo arm over 5 years

Risk ratio & 95% CI

Additional cases per 1000 HRT users over 5 year

50 - 59

8

1.3 (1.1 – 1.6)

3 (1 – 5)

a No differentiation was made between ischaemic and haemorrhagic stroke.

Other adverse reactions have been reported in association with oestrogen/progestogen treatment

- Gall bladder disease.

- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

- Probable dementia over the age of 65 (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In clinical studies in male volunteers doses up to 100 mg of drospirenone were well tolerated. Overdose may cause nausea and vomiting and withdrawal bleeding may occur in some women. There are no specific antidotes, and, treatment should be symptomatic