Ryeqo · 4.3 Contraindications · 1

HOS-287955 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile The most frequent adverse reactions, in patients being treated for uterine fibroids or endometriosis, were headache (13.2%), hot flush (10.3%) and uterine bleeding (5.8%). Adverse reactions listed in Table 4 are classified according to frequency and system organ class. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as 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), and not known (cannot be estimated from available data). Tabulated list of adverse reactions Table 4. Adverse reactions in patients with uterine fibroids and endometriosis Psychiatric disorders Common Irritability Libido decreased* Nervous system disorders Very common Headache Common Dizziness Vascular disorders Very common Hot flush Rare Hypertension Gastrointestinal disorders Common Nausea Uncommon Dyspepsia Skin and subcutaneous tissue disorders Common Alopecia Hyperhidrosis Night sweats Uncommon Angioedema Urticaria Musculoskeletal and connective tissue disorders Common Arthralgia Reproductive system and breast disorders Common Uterine bleeding** Vulvovaginal dryness Uncommon Breast cyst Uterine myoma expulsion * includes libido decreased, libido loss and libido disorder. ** includes menorrhagia (heavy menstrual bleeding), metrorrhagia (intermenstrual bleeding), vaginal haemorrhage, uterine haemorrhage, polymenorrhoea, and menstruation irregular. 12 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 national reporting system li

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HOS-287951 · has-contraindication-information · PDF-Seite 3

− Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. − Venous thromboembolic disorder, past or present (e.g. deep venous thrombosis, pulmonary embolism) (see section 4.4). − Arterial thromboembolic cardiovascular disease, past or present (e.g. myocardial infarction, cerebrovascular accident, ischemic heart disease) (see section 4.4). − Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency or activated protein C (APC)-resistance, including Factor V Leiden (see section 4.4). 3 − Known osteoporosis (see section 4.4). − Headaches with focal neurological symptoms or migraine headaches with aura (see section 4.4). − Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts). − Presence or history of liver tumours (benign or malignant) (see section 4.4). − Presence or history of severe hepatic disease as long as liver function values have not returned to normal (see section 4.4). − Pregnancy or suspected pregnancy (see section 4.6). − Genital bleeding of unknown aetiology (see section 4.4). − Concomitant use of hormonal contraceptives

HOS-287950 · has-indication-information · PDF-Seite 2

Ryeqo is indicated in adult women of reproductive age for: - treatment of moderate to severe symptoms of uterine fibroids, - symptomatic treatment of endometriosis in women with a history of previous medical or surgical treatment for their endometriosis (see section 5.1).

HOS-287953 · has-interaction-information · PDF-Seite 8

Recommendations regarding interactions with this medicinal product are based on evaluations of interactions for the individual components. Potential for other medicinal products to affect the components of Ryeqo Relugolix Oral P-glycoprotein (P-gp) inhibitors Concomitant use with oral P-gp inhibitors is not recommended. Relugolix is a substrate of P-gp (see section 5.2) and in an interaction study with erythromycin, a P-gp and moderate cytochrome P450 (CYP) 3A4 inhibitor, the area under the curve (AUC) and maximum concentration (Cmax) of relugolix were increased by 4.1-fold and 3.8-fold, respectively. Concomitant use of P-gp inhibitors may increase 8 the exposure of relugolix, including certain anti-infective medicinal products (e.g. erythromycin, clarithromycin, gentamicin, tetracycline), anti-fungal medicinal products (ketoconazole, itraconazole), antihypertensive medicinal products (e.g. carvedilol, verapamil), antiarrhythmic medicinal products (e.g. amiodarone, dronedarone, propafenone, quinidine), antianginal medicinal products (e.g. ranolazine), cyclosporine, human immunodeficiency virus (HIV) or hepatitis C virus (HCV) protease inhibitors (e.g. ritonavir, telaprevir). If concomitant use with once or twice daily oral P-gp inhibitors is unavoidable (e.g. azithromycin), take Ryeqo first, and separate dosing with the P-gp inhibitor by at least 6 hours and monitor patients more frequently for adverse reactions. Strong cytochrome P450 3A4 (CYP3A4) and/or P-gp inducers Concomitant use with strong CYP3A4 and/or P-gp inducers is not recommended. In a clinical interaction study with rifampicin, a strong CYP3A4 and P-gp inducer, the Cmax and AUC of relugolix were reduced by 23% and 55%, respectively. Medicinal products that cause strong CYP3A4 and/or P-gp induction, such as anticonvulsants (e.g. carbamazepine, topiramate, phenytoin, phenobarbital, primidone, oxcarbazepine, felbamate), anti-infective medicinal products (e.g. rifampicin, rifabutin, griseofulvin); St. John’s wort (Hypericum perforatum); bosentan and HIV or HCV protease inhibitors (e.g. ritonavir, boceprevir, telaprevir) and non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz), may reduce the plasma concentrations of relugolix and may result in a decrease in therapeutic effects. CYP3A4 inhibitors Concomitant use of relugolix with strong CYP3A4 inhibitors devoid of P-gp inhibition (voriconazole) did not increase the exposure of

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HOS-287954 · has-pregnancy-information · PDF-Seite 11

Women of childbearing potential Ryeqo inhibits ovulation in women taking the recommended dose and provides adequate contraception. A nonhormonal contraceptive method is recommended for use for 1 month after initiation of treatment and for 7 days following 2 or more missed consecutive doses. Concomitant use of hormonal contraceptives is contraindicated (see section 4.3). Women of childbearing potential must be advised that ovulation will return rapidly after discontinuing Ryeqo. A discussion with the patient, regarding appropriate contraceptive methods, must therefore take place prior to discontinuing treatment and alternative contraception needs to be started immediately after discontinuation of treatment (see section 4.4). Pregnancy There is a limited amount of data from the use of relugolix in pregnant women. Studies in animals have shown that exposure to relugolix early in pregnancy may increase the risk of early pregnancy loss (see section 5.3). Based on the pharmacological effects, an adverse effect on pregnancy cannot be excluded. Ryeqo is contraindicated during pregnancy (see section 4.3). Treatment should be discontinued if pregnancy occurs. There appears to be little or no increased risk of harmful effects in children born to women who have used estrogens and progestogens as an oral contraceptive inadvertently during early pregnancy. The increased risk of VTE during the postpartum period must be considered when re-starting Ryeqo (see section 4.4). Breast-feeding Small amounts of relugolix are excreted into human milk (see section 5.2). The effect on newborns/infants is unknown. Detectable amounts of estrogen and progestogens have been identified in the human milk of women receiving estrogen plus progestogen therapy. An effect on breastfeeding newborns/infants cannot be excluded. Ryeqo should not be used during breast-feeding. Fertility Ryeqo inhibits ovulation and often causes amenorrhoea. Ovulation and menstrual bleeding will return rapidly after discontinuing treatment (see section 5.1). 11

HOS-287952 · has-warning-information · PDF-Seite 4

Medical examination/consultation Prior to the initiation or reinstitution of this medicinal product, a complete medical history (including family history) must be taken. Blood pressure must be measured and a physical examination must be performed guided by the contraindications (see section 4.3) and warnings for use (see section 4.4). During treatment, periodic check-ups must be carried out according to standard clinical practice. Pregnancy must be ruled out prior to administering or re-initiation of Ryeqo. Risk of thromboembolic disorders The use of medicinal products containing an estrogen and a progestogen increases the risk of arterial or venous thromboembolism (ATE or VTE) compared with no use. The risk of ATE/VTE with this medicinal product has not been established. It contains doses of estrogen and progestogen lower than the doses used in combined hormonal contraceptives and are provided in combination with relugolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist that suppresses ovarian production of estrogen and progesterone. Estradiol levels with Ryeqo are in the range observed in the early follicular phase of the menstrual cycle (see section 5.1). If an ATE/VTE occurs, treatment must be discontinued immediately. This medicinal product is contraindicated in women with past or present venous or arterial thromboembolic disease (see section 4.3). Risk factors for venous thromboembolism (VTE) The risk for venous thromboembolic complications in women using a product with an estrogen and progestogen may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see Table 1 below). 4 Table 1. Risk factors for VTE Risk factor Comment Obesity (body mass index [BMI] over 30 kg/m2) Risk increases substantially as BMI rises. Prolonged immobilisation, major surgery or In these situations, it is advisable to discontinue major trauma use of the medicinal product (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Positive family history (VTE) ever in a sibling

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