Isturisa · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-098775 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile A total of 210 patients with Cushing´s disease has been treated with osilodrostat in the pivotal Phase III studies. The most frequent (incidence ≥ 10%) adverse reactions reported in the pivotal Phase III studies (C2301 and C2302) with Isturisa were adrenal insufficiency (see section 4.4 Warnings and precaution), fatigue, oedema, vomiting, nausea, decreased appetite headache, dizziness, hypotension, arthralgia, myalgia, tachycardia and blood testosterone increased. The safety profile of Isturisa was generally consistent across all types of Cushing’s syndrome studied in clinical trials. Tabulated list of adverse reactions Adverse reactions (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on the following 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). 7 Table 1 Adverse reactions System organ class Frequency Preferred term* category Endocrine disorders Very common Adrenal insufficiency Metabolism and nutrition disorders Very common Hypokalaemia, decreased appetite Nervous system disorders Very common Dizziness, headache Common Syncope Cardiac disorders Very common Tachycardia Vascular disorders Very common Hypotension Gastrointestinal disorders Very common Vomiting, nausea, diarrhoea, abdominal pain Skin and subcutaneous tissue disorders Very common Rash , hirsutism**, acne** Musculoskeletal and connective tissue Very common Myalgia, arthralgia disorders General disorders and administration Very common Fatigue, oedema site conditions Common Malaise Investigations Very common

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HOS-098771 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-098770 · has-indication-information · PDF-Seite 2

Isturisa is indicated for the treatment of endogenous Cushing’s syndrome in adults.

HOS-098773 · has-interaction-information · PDF-Seite 5

Potential pharmacodynamic interactions Co-administration of osilodrostat with other therapies known to affect the QT interval can lead to QT prolongation in patients with known cardiac rhythm disorders (see sections 4.4 and 5.1). A washout period should be considered when switching from other products known to affect the QT interval such as pasireotide or ketoconazole. Effects of other medicinal products on the pharmacokinetics of osilodrostat The potential for clinical drug-drug interactions (DDI) with concomitantly administered medicinal products that inhibit transporters or a single CYP or UGT enzyme is low (see section 5.2). Strong enzyme inhibitors Caution is advised when co-administered medicinal products that strongly inhibit multiple enzymes are introduced or discontinued during osilodrostat treatment (see section 4.4). Strong enzyme inducers Caution is advised when co-administered medicinal products that strongly induce multiple enzymes (e.g. rifampin) are introduced or discontinued during osilodrostat treatment (see section 4.4). Effects of osilodrostat on the pharmacokinetics of other medicinal products Because osilodrostat and its major metabolite M34.5 may inhibit and/or induce multiple enzymes and transporters, general caution is advised when osilodrostat is co-administered with sensitive enzyme or transporter substrates with a narrow therapeutic index. Available interaction data is summarised below (see also section 5.2). 5 Clinical studies In a healthy volunteer study (n=20) using a single dose of 50 mg osilodrostat and a probe drug cocktail, osilodrostat was found to be a mild inhibitor of CYP2D6 and CYP3A4/5, a mild to moderate inhibitor of CYP2C19, and a moderate inhibitor of CYP1A2. - CYP2D6 – area under the curve (AUC) geometric mean ratio of 1.5 for dextromethorphan (CYP2D6 substrate) when dosed with osilodrostat compared to when dosed alone. - CYP3A4 – AUC geometric mean ratio of 1.5 for midazolam (CYP3A4 substrate) when dosed with osilodrostat compared to when dosed alone. - CYP2C19 –AUC geometric mean ratio of 1.9 for omeprazole (CYP2C19 substrate) when dosed with osilodrostat compared to when dosed alone. However, an in vitro signal of time-dependent inhibition has been observed, thus the consequence following repeated dosing is unclear. Osilodrostat should be used with caution when co-administered with sensitive CYP2C1

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HOS-098774 · has-pregnancy-information · PDF-Seite 6

Women of childbearing potential Based on preclinical data, osilodrostat may cause foetal harm when administered to a pregnant woman. A pregnancy test before initiating treatment is recommended in women of childbearing potential. Women of childbearing potential have to use effective contraception during and for at least one week after treatment. If hormonal contraceptives other than the oral combination of ethinylestradiol and levonorgestrel are used, an additional barrier method of contraception is recommended (see section 4.5). Isturisa should not be used in women of childbearing potential not using contraception. Pregnancy There are no or limited amount of data from the use of osilodrostat in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Isturisa should not be used during pregnancy. 6 Breast-feeding It is unknown whether osilodrostat/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Isturisa and for at least one week after treatment. Fertility There is no information on the effect of osilodrostat on human fertility. Animal studies have shown effects on the menstrual cycle and reduced female fertility in rats (see section 5.3).

HOS-098772 · has-warning-information · PDF-Seite 4

Hypocortisolism Inhibition of cortisol synthesis by osilodrostat has led to hypocortisolism-related events such as cortisol withdrawal syndrome (symptomatic decrease of cortisol levels, but still above the lower limit of the normal range) and adrenal insufficiency (cortisol levels below the normal range). Cortisol levels should be monitored at regular intervals (see section 4.2), since hypocortisolism-related events can occur at any time during treatment and after treatment discontinuation. Additional monitoring is recommended especially during conditions of increased cortisol demand, such as physical or psychological stress, or during changes in concomitant medications that may affect osilodrostat exposure (see section 4.5). It is recommended to use laboratory methods that do not exhibit significant cross-reactivity with cortisol precursors such as 11-deoxycortisol that may increase during osilodrostat treatment. Patients should be alerted to the signs and symptoms associated with hypocortisolism (e.g. nausea, vomiting, fatigue, abdominal pain, loss of appetite and dizziness). Symptomatic patients should be monitored for hypotension, hyponatraemia, hyperkalaemia and/or hypoglycaemia. If hypocortisolism is suspected, cortisol levels should be measured and temporary dose reduction or interruption of osilodrostat considered. After osilodrostat discontinuation, cortisol suppression may persist for months, irrespective of osilodrostat administered dose, and might require additional monitoring. If necessary, corticosteroid substitution should be initiated. Isturisa may be resumed after resolution of symptoms at a lower dose, provided that cortisol levels are above the lower limit of normal in the absence of glucocorticoid substitution. QTc prolongation In a thorough QT study, osilodrostat was associated with a dose-dependent QT interval prolongation (mean maximum estimated QTcF increase by +5.3 ms at the highest recommended dose of 30 mg) which may cause cardiac arrhythmias (see section 5.1). Adverse reactions of QT prolongation and clinically relevant ECG findings have been reported in clinical studies. An electrocardiogram (ECG) should be performed prior to the start of Isturisa treatment, within one week after treatment initiation, and as clinically indicated thereafter. If the QTc interval exceeds 480 ms prior to or during treatment, cardiology consultation is recommended. Temporary dose reduction or interruption may be required. Any hypokalaemia, h

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