Ogsiveo · 4.6 Fertility, pregnancy and lactation · 1

HOS-100534 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most common adverse reactions are: diarrhoea (85%), rash (65%), ovarian toxicity in women of childbearing potential (60%), nausea (59%), fatigue (50%), hypophosphataemia (50%), headache (40%), and stomatitis (40%). The most frequently reported serious adverse reaction was ovarian toxicity (premature menopause, 3%). The most common severe adverse reactions were diarrhoea (16%) and hypophosphataemia (13%). 8 Permanent discontinuation of nirogacestat due to an adverse event occurred in 19% of patients. The most common adverse reactions leading to discontinuation were diarrhoea (5%), ovarian toxicity (5%), and increased ALT (3%). The frequency of dose interruption of nirogacestat due to adverse reactions was 59%. The most common adverse reactions leading to dose interruption were diarrhoea (11%), rash maculo- papular (10%), hypophosphatemia (6%) and nausea (5%). The frequency of dose reduction of nirogacestat due to adverse reactions was 44%. The most common adverse reactions leading to dose reduction were diarrhoea (9%), rash maculo-papular (6%), stomatitis (3%), and hypophosphatemia (3%). Tabulated list of adverse reactions Unless otherwise stated, the frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 88 patients exposed to nirogacestat 150 mg twice daily during a median duration of 21.5 months in clinical studies. The adverse reactions are ranked under heading of frequency using 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 2: Adverse reactions reported System organ class Adverse reaction All grades Grades 3-4 Gastrointestinal disorders Diarrhoea Very common Very common Nausea Very common Common Stomatitisa Very common Common Dry mouth Very common -- Skin and subcutaneous Rashb Very common Common disorders Alope

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HOS-100530 · has-contraindication-information · PDF-Seite 4

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Pregnancy (see sections 4.4 and 4.6) - Women of childbearing potential not using highly effective contraception (see sections 4.4 and 4.6) - Breast-feeding (see section 4.6) 4

HOS-100529 · has-indication-information · PDF-Seite 3

Ogsiveo as monotherapy is indicated for the treatment of adult patients with progressing desmoid tumours who require systemic treatment.

HOS-100532 · has-interaction-information · PDF-Seite 6

Interaction studies have only been performed in adults. Nirogacestat is primarily metabolized by CYP3A4 and is a substrate of P‑glycoprotein (P-gp). Agents that may increase nirogacestat serum concentrations Effect of moderate and strong CYP3A4 inhibitors In a clinical study, co‑administration of itraconazole (a strong CYP3A4 inhibitor and P‑gp inhibitor) increased nirogacestat Cmax by 2.5‑fold and AUC by 8.2‑fold. Co‑administration with moderate CYP3A4 inhibitors is also expected to result in clinically relevant increases in exposure. Concomitant use with strong inhibitors of CYP3A4 (e.g., clarithromycin, oral ketoconazole, itraconazole) and moderate inhibitors of CYP3A4 (e.g., erythromycin and fluconazole) should therefore be avoided. Alternative concomitant medicinal products with no or minimal CYP3A4 inhibition should be considered. If therapeutic alternatives are not available, Ogsiveo should be immediately interrupted for the period of time in which a strong or moderate CYP3A4 inhibitor is given. 6 Patients should avoid consuming grapefruit and grapefruit juice when taking Ogsiveo since they include inhibitors of CYP3A4 (see section 4.2). Agents that may decrease nirogacestat serum concentrations Effect of strong and moderate CYP3A4 inducers The effects of CYP3A4 inducers on nirogacestat exposure have not been evaluated in a clinical study. Moderate and strong inducers are expected to result in clinically relevant decreases in exposure of nirogacestat that could lead to reduced efficacy. Concomitant treatment with strong inducers of CYP3A4 (e.g., carbamazepine, phenytoin, rifampicin, phenobarbital and St. John’s wort) and moderate CYP3A inducers (e.g., efavirenz and etravirine) should therefore be avoided. In patients for whom CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be selected. Effect of acid‑reducing agents Nirogacestat has pH‑dependent solubility, with substantially reduced solubility at pH greater than 6.0. The effects of acid reducing agents (i.e., H2‑receptor antagonists, proton pump inhibitors and antacids) on nirogacestat exposure have not been evaluated in a clinical study, however, co‑administration of these medicinal products may reduce the bioavailability of nirogacestat. Concomitant use of Ogsiveo with proton pump inhibitors and H2 blockers is not recommended. However, if concomitant use with acid reducing agents cannot be

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HOS-100533 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential/Contraception in males and females Women of childbearing potential and men with female partners of childbearing potential should be advised to avoid pregnancy while on Ogsiveo (see section 4.4). 7 Women of childbearing potential must use highly effective contraceptive methods during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo (see section 4.4). It is unknown whether nirogacestat reduces the effectiveness of systemically acting hormonal contraceptives. Patients should be advised to use at least one highly effective method of contraception (such as an intrauterine device) or two complementary forms of contraception including a barrier method during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo. Women of childbearing potential should be advised to inform their healthcare provider immediately of a known or suspected pregnancy, and they must stop taking Ogsiveo if they become pregnant. Women of childbearing potential should not donate eggs (oocytes) during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo. Male patients with female partners of childbearing potential must use highly effective contraceptive methods during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo (see section 4.4). Male patients should not donate sperm during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo. Pregnancy Based on findings from animal studies and its mechanism of action, Ogsiveo may cause foetal harm when administered to a pregnant woman. Ogsiveo is contraindicated in pregnant women (see sections 4.3 and 5.3). Women of childbearing potential must have a negative pregnancy test prior to initiating Ogsiveo treatment. Pregnancy testing during treatment with Ogsiveo should be considered for women of childbearing potential experiencing amenorrhoea. Patients should be advised of the potential risk to a foetus. If a patient becomes pregnant while taking Ogsiveo, treatment must be discontinued. A spontaneous abortion was reported by a woman in the DeFi study who conceived while receiving nirogacestat. Breast‑feeding There are no data regarding the presence of nirogacestat or its metabolites in either human or animal milk or its effects on a breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, women must not breastfeed during tre

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HOS-100531 · has-warning-information · PDF-Seite 5

Diarrhoea Diarrhoea was reported in patients receiving nirogacestat (see section 4.8). Patients who experience diarrhoea during treatment with nirogacestat should be monitored and managed using anti‑diarrhoeal medicinal products. For Grade 3 diarrhoea that persists for ≥ 3 days despite maximal medical therapy, nirogacestat should be withheld until diarrhoea is resolved to Grade ≤ 1 or baseline, then it should be restarted at 100 mg twice daily (see section 4.2). Skin and subcutaneous tissue disorders Dermatologic reactions, including maculopapular rash, folliculitis, and hidradenitis, were reported in patients receiving nirogacestat (see section 4.8). Patients should be monitored for dermatologic reactions throughout the course of treatment and managed as clinically indicated. For Grade 3 dermatologic reactions, nirogacestat should be withheld until resolved to Grade ≤ 1 or baseline, then it should be restarted at a dose of 100 mg twice daily (see section 4.2). Ovarian toxicity Ovarian toxicity was reported in female patients of childbearing potential receiving nirogacestat (see section 4.8). Ovarian toxicity, identified based on abnormal reproductive hormone levels or peri‑menopausal symptoms, was reported in 75% of women of childbearing potential receiving nirogacestat in the DeFi study. Ovarian toxicity has been reported to resolve in 79% of women of childbearing potential during treatment. Follow up information is available for all but two out of 27 patients; after stopping treatment, ovarian toxicity was reported to resolve in all women of childbearing potential for whom data are available (see section 4.8). Effects of nirogacestat on human fertility are unknown. Based on findings from animal studies, female fertility may be impaired. Women of childbearing potential should be advised about the risk of ovarian toxicity before initiating treatment with nirogacestat. Patients should be monitored for changes in menstrual cycle regularity or the development of symptoms of oestrogen deficiency, including hot flashes, night sweats, and vaginal dryness. Electrolyte abnormalities Electrolyte abnormalities, including hypophosphataemia and hypokalaemia, were reported in patients receiving nirogacestat (see section 4.8). Phosphate and potassium levels should be monitored regularly and supplemented as necessary. For Grade 3 hypophosphataemia persisting for ≥ 7 days despite maximal replacement therapy, nirogacestat should be withheld until resolved to Grade

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