Zoely · 4.4 Special warnings and precautions for use · 1

HOS-095652 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile Six multi-centre clinical trials of up to one-year duration were used to evaluate safety of Zoely. In total 3,434 women, aged 18-50, were enrolled and completed 33,828 cycles. Most commonly reported adverse reactions in these clinical trials were acne (15.4%) and withdrawal bleeding irregular (9.8%). An increased risk for venous and arterial thromboembolism, causative of serious adverse events has been observed with the use of CHCs (see section 4.4) Tabulated list of adverse reactions Possibly related adverse reactions that have been reported in clinical trials or during post-marketing use with Zoely are listed in the table below. Adverse reactions are listed according to the MedDRA system organ class and ranked under frequency groupings using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000). 13 Table: List of adverse reactions Adverse reaction in MedDRA Term1 System organ class Very common Common Uncommon Rare Metabolism and increased decreased nutrition disorders appetite, fluid appetite retention Psychiatric disorders decreased increased libido libido, depression/ depressed mood, mood altered Nervous system headache, cerebrovascular disorders migraine accident, transient ischaemic attack, disturbance in attention Eye disorders

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HOS-095648 · has-contraindication-information · PDF-Seite 5

CHCs must not be used in the following conditions. Should any of the conditions appear for the first time during Zoely use, the medicinal product should be stopped immediately. • Presence or risk of venous thromboembolism (VTE) o Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE]). o Known hereditary or acquired predisposition for venous thromboembolism, such as activated protein C (APC)-resistance (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency. o Major surgery with prolonged immobilisation (see section 4.4). o A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4). • Presence or risk of arterial thromboembolism (ATE) o Arterial thromboembolism - current ATE, history of ATE (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris). o Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack [TIA]). o Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant). o History of migraine with focal neurological symptoms. o 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. • Pancreatitis or a history thereof if associated with severe hypertriglyceridaemia. • Presence or history of severe hepatic disease as long as liver function values have not returned to normal. • Presence or history of liver tumours (benign or malignant). • Known or suspected sex steroid-influenced malignancies (e.g., of the genital organs or the breasts). • Meningioma or history of meningioma. • Undiagnosed vaginal bleeding. • Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 5

HOS-095647 · has-indication-information · PDF-Seite 2

Oral contraception. The decision to prescribe Zoely should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Zoely compares with other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4).

HOS-095650 · has-interaction-information · PDF-Seite 11

Interactions Note: The prescribing information of concomitant medicinal products should be consulted to identify potential interactions. Influence of other medicinal products on Zoely Interactions between oral contraceptives and enzyme-inducing medicinal products may lead to breakthrough bleeding and/or contraceptive failure. Hepatic metabolism: Interactions can occur with substances that induce CYP450 enzymes, resulting in reduced concentrations of sex hormones and decreased effectiveness of combined oral contraceptives, including Zoely. These substances are represented mostly with anticonvulsants (e.g. carbamazepine, topiramate, phenytoin, phenobarbital, primidone, oxcarbazepine, felbamate); anti-infective drugs (e.g. rifampicin, rifabutin, griseofulvin); St. John’s wort; bosentan and HIV or Hepatitis C virus (HCV) protease inhibitors (e.g. ritonavir, boceprevir, telaprevir) and non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz). Enzyme induction can occur after a few days of treatment. Maximal enzyme induction is generally 11 observed within a few weeks. After drug therapy is discontinued, enzyme induction can last for about 28 days. A barrier contraceptive method should also be used during the concomitant use of an enzyme inducer, and for 28 days after its discontinuation. In case of long-term treatment with hepatic enzyme-inducing substances another method of contraception should be considered. If concomitant drug administration runs beyond the end of the active tablets in the current blister pack, the next blister pack should be started right away without the usual placebo tablet interval. Concomitant administration of strong (e.g. ketoconazole, itraconazole, clarithromycin) or moderate (e.g. fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may increase the serum concentrations of oestrogens or progestogens. Medicinal product interaction studies were not performed with Zoely, but two studies with rifampicin and ketoconazole, respectively, were performed with a higher dosed nomegestrol acetate-estradiol combination (nomegestrol acetate 3.75 mg + 1.5 mg estradiol) in post-menopausal women. Concomitant use of rifampicin decreases the AUC0-∞ of nomegestrol acetate by 95 % and increases the AUC0-tlast of estradiol by 25 %. Concomitant use of ketoconazole (200 mg single dose) does not modify estradiol metabolism whereas increases in the peak concentration (85 %) and AUC0-∞ (115

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HOS-095651 · has-pregnancy-information · PDF-Seite 12

Pregnancy Zoely is not indicated during pregnancy. If pregnancy occurs while taking Zoely, further intake should be stopped. Most epidemiological studies have revealed neither an increased risk of birth defects in infants born to women who used ethinylestradiol-containing COCs prior to pregnancy, nor a teratogenic effect when ethinylestradiol-containing COCs were taken inadvertently during early pregnancy. 12 Clinical data on a limited number of exposed pregnancies indicate no adverse effect of Zoely on the foetus or neonate. In animal studies, reproductive toxicity has been observed with the nomegestrol acetate / estradiol combination (see preclinical safety data in section 5.3). The increased risk of VTE during the postpartum period should be considered when re-starting Zoely (see section 4.2 and 4.4). Breast-feeding Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the breast milk, but there is no evidence that this adversely affects infant health. Breast-feeding may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should not be recommended until the breast- feeding mother has completely weaned her child and an alternative method of contraception should be proposed to women wishing to breastfeed. Fertility Zoely is indicated for the prevention of pregnancy. For information on return to fertility, see section 5.1.

HOS-095649 · has-warning-information · PDF-Seite 6

Warnings If any of the conditions or risk factors mentioned below is present, the suitability of Zoely should be discussed with the woman. In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of Zoely should be discontinued. All data presented below are based upon epidemiological data obtained with CHCs containing ethinylestradioland apply to Zoely. 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. Zoely may have a risk of VTE in the same range as observed with CHC containing levonorgestrel. The decision to use any product other than one known to have the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, 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). • Epidemiological studies in women who use low dose (< 50 micrograms ethinylestradiol) CHC have found that out of 10,000 women between 6 and 12 will develop a VTE in one year. • It is estimated that out of 10,000 women who use a levonorgestrel-containing CHC about 61 will develop a VTE in one year. • The number of VTEs per year with low dose CHCs is fewer than the number expected in women during pregnancy or in the postpartum period. • VTE may be fatal in 1-2 % of cases. • Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, or retinal veins and arteries. Risk factors for VTE The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table). Zoely is contraindicated if a

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