Evra · 4.3 Contraindications · 1

HOS-093370 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile The most commonly reported adverse reactions in clinical trials were headache, nausea, and breast tenderness, occurring in approximately 21.0%, 16.6%, and 15.9% of patients, respectively. Adverse reactions that may occur at the beginning of treatment but usually diminish after the first three cycles include spotting, breast tenderness and nausea. 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. 13 Tabulated list of adverse reactions Safety was evaluated in 3 322 sexually active women who participated in three Phase III clinical trials, which were designed to evaluate contraceptive efficacy. These subjects received six or 13 cycles of contraception (EVRA or oral contraceptive comparator), took at least one dose of study medicinal product and provided safety data. Table 1 below reflects the adverse reactions reported in clinical trials and from post-marketing experience. Frequency MedDRA convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data). Table 1: Frequency of adverse reactions System Organ Class Adverse reaction Frequency Infections and infestations common (Vulvo) vaginal fungal infection Vaginal candidiasis rare Rash pustular* Application site pustules Neoplasms benign, malignant and unspecified (incl cysts and polyps) rare Hepatic neoplasm*† Breast cancer*† Cervix carcinoma*† Hepatic adenoma*† Uterine leiomyoma Fibroadenoma of breast Immune system disorders uncommon Hypersensitivity rare Anaphylactic reaction* not known Exacerbation of symptoms of hereditary and acquired angi

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HOS-093366 · has-contraindication-information · PDF-Seite 5

Combined hormonal contraceptives (CHCs) should not be used in the following conditions. If one of these disorders occurs during the use of EVRA, EVRA must be discontinued immediately. • Presence or risk of venous thromboembolism (VTE) • Venous thromboembolism – current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE]); • Known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance, (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency; • Major surgery with prolonged immobilisation (see section 4.4); • A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4); 5 • Presence or risk of arterial thromboembolism (ATE) • Arterial thromboembolism – current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris); • Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA); • Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant); • History of migraine with focal neurological symptoms; • A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) or to the presence of one serious risk factor such as: - diabetes mellitus with vascular symptoms - severe hypertension - severe dyslipoproteinaemia • Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 • Known or suspected carcinoma of the breast • Carcinoma of the endometrium or other known or suspected oestrogen-dependent neoplasia • Abnormal liver function related to acute or chronic hepatocellular disease • Hepatic adenomas or carcinomas • Undiagnosed abnormal genital bleeding • Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, medicinal products containing glecaprevir/pibrentasvir or sofo

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HOS-093365 · has-indication-information · PDF-Seite 2

Female contraception EVRA is intended for women of fertile age. The safety and efficacy has been established in women aged 18 to 45 years. The decision to prescribe EVRA should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with EVRA compares with other CHCs (see sections 4.3 and 4.4).

HOS-093368 · has-interaction-information · PDF-Seite 11

Note: The prescribing information of concomitant medicinal products should be consulted to identify potential interactions. 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 ethinyl estradiol-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 ethinyl estradiol-containing medications such as CHCs (see section 4.3). Therefore, EVRA-users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with these combination drug regimens. EVRA can be restarted 2 weeks following completion of treatment with these combination drug regimens. 11 Effects of other medicinal products on EVRA Interactions can 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. The following interactions have been reported in the literature. Substances increasing the clearance of CHCs (diminished efficacy of CHCs by enzyme-induction),e.g.: Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, modafinil, and HIV medications ritonavir, nevirapine and efavirenz; and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John's Wort (hypericum perforatum). Management Enzyme induction may be observed after a few days of treatment. Maximal enzyme induction is generally seen in about 10 days but may then be sustained for at least 4 weeks after the cessation of medicinal product therapy. Short-term A woman on short-term treatment with medicinal products that induce hepatic drug metabolising enzymes or individual active substances that induce these enzymes should temporarily use a barrier method in addition to EVRA, i.e. during the time of concomitant medicinal product administration and for 28 days after their discontinuation. If concomitant medicinal product administration extends be

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HOS-093369 · has-pregnancy-information · PDF-Seite 13

Pregnancy EVRA is not indicated during pregnancy. Epidemiological studies indicate no increased risk of birth defects in children born to women who used combined oral contraceptives prior to pregnancy. The majority of recent studies also do not indicate a teratogenic effect when combined oral contraceptives are used inadvertently during early pregnancy. Limited data on the outcomes of exposed pregnancies in women using EVRA do not allow for conclusions about its safety during pregnancy. Animal studies have shown undesirable effects during pregnancy and lactation (see section 5.3). Based on these animal data, undesirable effects due to hormonal action of the active compounds cannot be excluded. However, general experience with combined oral contraceptives during pregnancy did not provide evidence for an actual undesirable effect in humans. If pregnancy occurs during use of EVRA, EVRA should be stopped immediately. The increased risk of VTE during the postpartum period should be considered when re-starting EVRA (see sections 4.2 and 4.4). Breast-feeding Breast-feeding may be influenced by combined hormonal contraceptives as they may reduce the quantity and change the composition of breast milk. Therefore, the use of EVRA is not to be recommended until the breast-feeding mother has completely weaned her child. Fertility Women may experience a delay in conception following discontinuation of EVRA.

HOS-093367 · has-warning-information · PDF-Seite 6

Warnings If any of the conditions/risk factors mentioned below is present, the suitability of EVRA should be discussed with the woman. In the event of aggravation, or first appearance of any of the conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of EVRA should be discontinued. There is no clinical evidence indicating that a transdermal patch is, in any aspect, safer than combined oral contraceptives. EVRA is not indicated during pregnancy (see section 4.6). Risk of venous thromboembolism (VTE) The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as EVRA may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with EVRA, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more. In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below). 6 It is estimated that out of 10,000 women who use a low dose CHC that contains levonorgestrel, about 6 1 will develop a VTE in one year. Studies have suggested that the incidence of VTE in women who used EVRA is up to 2-fold higher than in users of CHCs that contain levonorgestrel. This corresponds to between about 6 and 12 VTEs in a year out of 10,000 women who use EVRA. In both cases, the number of VTEs per year is fewer than the number expected in women during pregnancy or in the postpartum period. VTE may be fatal in 1-2% of cases. Number of VTE events per 10,000 women in one year Number of VTE events 14 12 10 8 6 4 2 0 Non-CHC user (2 events) Levonorgestrel-containing CHC (5-7 Norelgestromin-containing CHC (6-12

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