Intrarosa · 4.4 Special warnings and precautions for use · 1

HOS-097745 · has-adverse-reaction-information · PDF-Seite 7

Summary of safety profile The most frequently observed adverse reaction was vaginal discharge. This is due to melting of the hard fat used as vehicle, added to the expected increase in vaginal secretions due to treatment. It is not required to stop Intrarosa if vaginal discharge occurs (see section 4.4). Tabulated list of adverse reactions Adverse reactions observed with prasterone 6.5 mg pessaries obtained from clinical studies are tabulated in Table 1 below. Table 1: Adverse reactions observed with prasterone 6.5 mg pessaries in clinical studies MedDRA System Organ Common Uncommon Class (≥ 1/100 to < 1/10) (≥ 1/1,000 to < 1/100) General disorders and Application site discharge - administration site conditions Reproductive system and Abnormal Pap smear (mostly Cervical/ uterine polyps breast disorders ASCUS or LGSIL) Breast mass (benign) Investigations Weight fluctuation - 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. • Any 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). • Results of the largest randomised placebo-controlled study (WHI-study) and largest epidemiological study (MWS) are presented. 7 Million Women study– Estimated additional risk of breast cancer after 5 years’ use Age Additional cases per 1000 never- Risk ratio & Additional cases per 1000 HRT range users of HRT over a 5-year period 1 95%CI# users over 5 years (95%CI) (years) Oestrogen only HRT 50-65 9-12 1.2 1-2 (0-3) #Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer

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HOS-097741 · has-contraindication-information · PDF-Seite 3

• Hypersensitivity to the active substance or to the excipient listed in section 6.1; • Undiagnosed genital bleeding; • Known, past or suspected breast cancer; • Known or suspected oestrogen-dependent malignant tumours (e.g endometrial cancer); • Untreated endometrial hyperplasia; • Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal; • Previous or current venous thromboembolism (VTE) (deep vein thrombosis, pulmonary embolism); • Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4); • Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction); • Porphyria.

HOS-097740 · has-indication-information · PDF-Seite 2

Intrarosa is indicated for the treatment of vulvar and vaginal atrophy in postmenopausal women having moderate to severe symptoms.

HOS-097743 · has-interaction-information · PDF-Seite 6

Concomitant use with systemic HRT (oestrogen-only or oestrogen-progestagen combination or androgen treatment) or vaginal oestrogens has not been investigated and is therefore not recommended. 6

HOS-097744 · has-pregnancy-information · PDF-Seite 7

Pregnancy Intrarosa is not indicated in pre-menopausal women of child-bearing age, including pregnancy. If pregnancy occurs during treatment with Intrarosa, the treatment should be withdrawn immediately. There are no data on the use of Intrarosa in pregnant women. No studies in animals were performed with regard to the reproductive toxicity (see section 5.3). The potential risk in humans is unknown. Breast-feeding Intrarosa is not indicated during breast-feeding. Fertility Intrarosa is not indicated in fertile women.

HOS-097742 · has-warning-information · PDF-Seite 3

For the treatment of postmenopausal symptoms, Intrarosa 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 reassessed at least every 6 months and Intrarosa should only be continued as long as the benefit outweighs the risk following discussions with their doctor. Medical examination/follow-up Before initiating Intrarosa, 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 special warnings and precautions for use according to the decision of their doctor. 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 (see ‘Breast cancer’ below). Investigations, including Pap smears and blood pressure measurements should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual. 3 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 Intrarosa, 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 contraindication is discovered and in the following situation: – Jaundice or deterioration in liver function – Significant increase in blood pressure – New onset of migraine-type headache – Pregnancy. Endometrial hyperplasia and carcinoma • Estrogen is a metabolite of prasterone. In women with an intact

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