Irish Medicines Board

Summary of Product Characteristics 1 NAME OF THE MEDICINAL PRODUCT Utrogestan 100 mg soft capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule contains 100 mg progesterone as the active ingredient. Excipient(s) with known effect: contains 1.0mg soya bean lecithin. For the full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM Soft capsule (capsules) Oblate, spheroid, white, opaque soft gelatin capsules containing a white paste.

4 CLINICAL PARTICULARS 4.1 Therapeutic Indications As the progesterone component in hormonal replacement therapy for the menopause.

4.2 Posology and method of administration The recommended dose is 200 mg at bedtime, for 12 days in the last half of each therapeutic cycle (beginning on Day 15 and ending on Day 26).

4.3 Contraindications Confirmed pregnancy (see Section 4.6); Lactation; Severe disturbances of liver function (including porphyria) or past history as long as liver function tests have not returned to normal, previous or existing liver tumours; Rotor syndrome; Dubin-Johnson syndrome; Severe cardiac disease, Severe renal disease; Jaundice or general pruritus during a previous pregnancy; Active or past deep venous thrombosis; Arterial thromboembolic disorders or a past history of these conditions; Sickle cell anaemia; Severe diabetes with vascular changes; Suspected or existing hormone dependent disorders or tumours of the uterus, breast or ovaries;

______________________________________________________________________________________________________________________ Date Printed 28/04/2014 CRN 2145907 page number: 1

Irish Medicines Board

Past history of breast cancer Undiagnosed irregular vaginal bleeding; Disturbances of lipid metabolism; History of herpes gestations; untreated endometrial hyperplasia, Porphyria, otosclerosis with deterioration in previous pregnancies; Endometriosis; Hypersensitivity to soya lecithin and any of the ingredients.

4.4 Special warnings and precautions for use For the treatment of post menopausal 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. Utrogestan 100mg Capsules are intended to be co-prescribed with an oestrogen product as HRT. The prescribing information for the co-prescribed oestrogen product should be referred to for information about the overall risks of HRT. Before starting treatment pregnancy must be excluded. Prior to treatment, a thorough personal and family general medical history should be taken. Patients should have a physical examination with special emphasis on the body weight, blood pressure, heart, breasts, pelvic organs with an endometrial assessment if indicated, the legs and skin. Follow-up examinations are recommended at least six-monthly during treatment. Conditions which need supervision Special supervision is needed in patients presenting the conditions below or having conditions that are known to aggravate during previous hormone treatment or pregnancy, as these conditions may re-occur or be aggravated under treatment with Utrogestan. These conditions are: Multiple sclerosis, Epilepsy, Diabetes mellitus with or without vascular involvement, Benign breast disease, Risk factors for oestrogen-dependent tumours, e.g. 1st degree heredity for breast cancer Liver disorders Hypertension, Cardiac, hepatic or renal dysfunction, Migraine, Asthma, Chorea minor, Tetany Otosclerosis, Leiomyoma (uterine fibroids) or endometriosis, History of, or risk factors for thromboembolic disorders,

______________________________________________________________________________________________________________________ Date Printed 28/04/2014 CRN 2145907 page number: 2

Irish Medicines Board

Systemic lupus erythematosus, History of endometrial hyperplasia. Reasons for immediate withdrawal of therapy Treatment should be stopped at once if migrainous or frequent and unusually severe headaches occur for the first time, or if there are other symptoms that are possible prodromata of vascular occlusion, e.g. sudden visual disturbances. Treatment should also be stopped at once if jaundice, cholestasis, hepatitis or pregnancy occurs, or if there is a significant rise in blood pressure an increase in epileptic seizures, or development of VTE. Endometrial Hyperplasia and Cancer Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding and spotting appears after some time on therapy, or continues after treatment has been discontinued, this should be investigated by endometrial biopsy, if necessary to exclude endometrial malignancy. 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)). Breast Cancer For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment. Combined oestrogen-progestagen therapy One randomised placebo-controlled trial, the (Women’s Health Initiative study (WHI), and epidemiological studies (including the Million Women Study (MWS) have reported an increased relative risk of breast cancer in women taking combined oestrogen-progestagen for HRT for several years (see Section 4.8) In the MWS, the relative risk of breast cancer with conjugated equine oestrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration. HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer. Women on therapy should have regular breast examinations and be instructed in self-breast examination. Regular mammographic investigations should be conducted where considered appropriate. Women with a strong family history of breast cancer should be carefully observed during treatment. Venous thromboembolism Epidemiological evidence suggests that use of hormone replacement therapy (HRT) is associated with an increased risk of developing deep vein thrombosis (DVT) or pulmonary embolism (PE). It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate =4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later. The increased risk of VTE means that caution should be exercised in using HRT in women who are likely to be at high risk from DVT or PE. Generally recognised risk factors for VTE include major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m2), and systemic lupus erythematosus (SLE). If venous thromboembolism 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 (eg, painful swelling of a leg, sudden pain in the chest, dyspnoea). There is no consensus about the role of varicose veins and VTE. The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. In cases of bed rest following elective surgery, consideration should be given to discontinuing treatment before operations (4-6 weeks beforehand) or following immobilisation and reinstating treatment after complete remobilisation of the patient. In patients with a history of VTE or known thrombotic state, the benefits of treatment with HRT will need to be carefully weighed against the risks. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

______________________________________________________________________________________________________________________ Date Printed 28/04/2014 CRN 2145907 page number: 3

Irish Medicines Board

Coronary artery disease (CAD) There is no evidence from randomised controlled clinical trials of cardiovascular benefit with continuous combined conjugated oestrogens and medroxyprogesterone acetate. Two large clinical trials (WHI and HERS, i.e., Heart and Estrogen/Progestin Replacement Study) showed a possible risk of increased cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining the effects in cardiovascular morbidity or mortality. Therefore it is uncertain whether these findings also extend to other HRT products. Stroke An increase in the incidence of stroke in patients taking HRT has been observed in the WHI trial with continuous combined oestrogens and MPA. Over a period of 5 years the estimated increase in cases of stroke was between 0 and 3 (best case 1) per 1000 users for women aged 50 to 59, and 1 to 9 (best case 4) per 1000 users for women aged 60 to 69. It is unknown whether the increased risk also extends to other HRT products. Other conditions There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post menopausal women or other HRT products. In rare cases benign, and in even rarer cases, malignant liver tumours leading in isolated cases to life threatening intraabdominal haemorrhage have been observed after the use of hormonal substances such as those contained in Utrogestan capsules. A hepatic tumour should be considered in the differential diagnosis if upper abdominal pain, enlarged liver, or signs of intra-abdominal haemorrhage occur.

4.5 Interaction with other medicinal products and other forms of interaction The metabolism of oestrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamezapin) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz). Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John’s wort (Hypericum Perforatum) may induce the metabolism of oestrogens and progestagens. The metabolism of oestrogen / progestagens may also be increased when concomitantly used with antibiotics and activated charcoal. Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.“

4.6 Fertility, pregnancy and lactation Utrogestan is not indicated during pregnancy. If pregnancy occurs during medication with Utrogestan, treatment should be withdrawn immediately. Clinically, data on a limited number of exposed pregnancies indicate no adverse effects of Utrogestan on the foetus. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of estrogens and progestogens indicate no teratogenic or foetotoxic effect. Utrogestan is not indicated during lactation. See section 4.3 Contraindications.

4.7 Effects on ability to drive and use machines This medicine may cause drowsiness or dizziness therefore care should be taken when driving or using machines.

______________________________________________________________________________________________________________________ Date Printed 28/04/2014 CRN 2145907 page number: 4

Irish Medicines Board

4.8 Undesirable effects Hormonal contraception should be stopped when the use of Utrogestan is started and the patient should be advised to take non-hormonal contraceptive precautions if required. During the first few months of treatment, breakthrough bleeding, spotting and breast tenderness or enlargement can occur. These are usually temporary and normally disappear after continued treatment. The most frequently reported adverse reactions are: skin disorders including pruritis, gastrointestinal disorders (including nausea, abdominal pain and bloating), liver disorders, cardiac disorders and reproductive disorders. Other symptoms known to occur are headache; migraine; dizziness; anxiety/depressive symptoms; alterations in body weight; oedema; hypertension; altered libido; changes in vaginal secretion; growth of pre-existing fibroids; chloasma or melasma which may be persistent. Some women are predisposed to cholestasis during steroid therapy. According to evidence from a large number of epidemiological studies and one randomised controlled trial (WHI), the overall risk of breast cancer increases with increasing duration of HRT in current of recent HRT users. Several epidemiological studies have reported an overall higher risk of breast cancer with oestrogen-progestagen combined HRT than with oestrogens alone. The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of breast cancer per 10,000 women years would be due to oestrogen-progestagen combined HRT. It should however be noted that the study was not conducted with micronized progesterone but with MPA. Due to the soy lecithin in the composition, there is a risk of unexpected hypersensitivity reactions (anaphylactic shock, hives).

4.9 Overdose No report of ill-effects from overdosage have been recorded and remedial action is generally unnecessary. If a large overdose is discovered within two to three hours and treatment seems desirable, gastric lavage is recommended. There is no specific antidote and treatment should be symptomatic.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Urogenital system and sex hormones ATC Code: G03DA04 Progesterone the naturally occurring hormone produced mainly in corpora lutea but also in the adrenal cortex has been formulated in a micronised form to facilitate absorption.

5.2 Pharmacokinetic properties It undergoes extensive first pass metabolism in the liver, the main product, 20 alpha-dihydropogesterone having significant activity with the same profile as progesterone. The T½ for elimination is about eight hours.

5.3 Preclinical safety data Not applicable.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sunflower oil, refined

______________________________________________________________________________________________________________________ Date Printed 28/04/2014 CRN 2145907 page number: 5

Irish Medicines Board

Soya bean lecithin Gelatin Glycerol (E422) Titanium dioxide (E171)

6.2 Incompatibilities Not applicable.

6.3 Shelf life 3 years.

6.4 Special precautions for storage Do not store above 25oC. Store in the original package.

6.5 Nature and contents of container Utrogestan 100 mg soft capsules is packed in PVC/Aluminium blisters of 10 capsules each. It is supplied in packs of three blisters containing 30 capsules.

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER Besins Healthcare Avenue Louise, 287 1050 Brussels Belgium

8 MARKETING AUTHORISATION NUMBER PA 1341/001/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 09 February 1988 Date of last renewal: 09 February 2008

10 DATE OF REVISION OF THE TEXT April 2014

______________________________________________________________________________________________________________________ Date Printed 28/04/2014 CRN 2145907 page number: 6