Etcamah · 4.1 Therapeutic indications · 1

HOS-100961 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The summary of the safety profile of Etcamah is based on pooled data from 263 patients who received Etcamah in combination with a CDK4/6 inhibitor in phase III (SERENA-6) and phase I (SERENA-1) studies. The most common adverse reactions (≥ 15%) for Etcamah in combination with a CDK4/6 inhibitor were neutropenia (59.7%), visual effects (40.7%), infections (38.4%), diarrhoea (21.3%), nausea (21.3%), anaemia (21.3%), fatigue (20.5%) bradycardia (19.8%) and leukopenia (15.6%). Among these, ADRs identified for Etcamah were visual effects (40.7%) and bradycardia (19.8%). The common Grade 3 or 4 adverse reactions (≥ 2%) for Etcamah in combination with a CDK4/6 inhibitor were neutropenia (46.4%), leukopenia (9.1%), anaemia (3.4%), infections (3.4%) and alanine aminotransferase increase (2.3%). The common serious adverse reactions (≥ 1%) reported in patients receiving Etcamah in combination with a CDK4/6 inhibitor included infections (3.4%) and pyrexia (1.1%). Adverse reactions leading to treatment discontinuation of Etcamah in patients receiving Etcamah in combination with a CDK4/6 inhibitor were neutropenia (0.4%) and electrocardiogram QT prolonged (0.4%). The most common adverse reactions (≥ 2%) leading to dose modification of Etcamah in patients receiving Etcamah in combination with a CDK4/6 inhibitor were infections (6.8%), neutropenia (6.5%), bradycardia (4.2%), electrocardiogram QT prolonged (3.4%), diarrhoea (2.3%), vomiting (2.3%) and visual effects (2.3%). Tabulated list of adverse reactions Adverse drug reactions identified for Etcamah in the Etcamah and CDK4/6 inhibitors combination are visual effects and bradycardia. Also included in Table 2 are adverse reactions, and their respective incidence, identified for the Etcamah and CDK4/6 inhibitors combination in the Etcamah in combination with a CDK4/6 inhibitor pool (n = 263). In SERENA-6, the median duration of exposure to Etcamah in combination with a CDK4/6 inhibitor was 15.54 months and to AI in combination with a CDK4/6 inhibitor was 7.36 months. The adverse reaction frequencies from clinical studies are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have causes other than the drug, such as the disease, other medication or unrelated causes. Adverse reactions are listed by MedDRA System Organ Class (SOC) and by descending frequency of the MedDRA grouped term. Frequencies are defined as: very common (≥

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HOS-100957 · has-contraindication-information · PDF-Seite 4

Breast-feeding (see section 4.6). Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4

HOS-100956 · has-indication-information · PDF-Seite 2

Etcamah in combination with a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) is indicated for the treatment of adult patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer upon detection of ESR1-mutation and without disease progression during first-line endocrine therapy in combination with a CDK4/6 inhibitor (for biomarker based patient-selection, see section 4.2 and 5.1). In pre- or peri-menopausal women and in men, Etcamah plus a CDK4/6 inhibitor should be combined with a luteinizing hormone releasing hormone (LHRH) agonist or antagonist.

HOS-100959 · has-interaction-information · PDF-Seite 5

Camizestrant is a reversible inhibitor of CYP3A4/5 and CYP2B6 and cause inhibition of drug transporters P-gp, BCRP and OATP1B1. Camizestrant is a potent, time-dependent, irreversible inhibitor of CYP2C9 and CYP2C19. Camizestrant is a substrate for CYP3A4/5 and P-gp. Effects of other medicinal products on camizestrant CYP3A4/5 inducers The exposure to camizestrant is expected to decrease if co-administered with moderate and strong CYP3A4/5 inducers. Clinically, a single 75 mg camizestrant dose co-administered orally with repeat doses of carbamazepine, a strong CYP3A4/5 inducer, resulted in camizestrant geometric mean ratios for Cmax and AUC of 0.41 [90% CI: 0.37,0.46] and 0.29 [90% CI: 0.28,0.32], respectively. The co- administration of camizestrant and a strong CYP3A4/5 inducer (including but not limited to: carbamazepine, phenytoin, rifampicin and St John’s Wort) should be avoided. An alternative medicinal product with no or weak potential to induce CYP3A4/5 should be considered. When co-administering camizestrant in combination with ribociclib, plus a moderate CYP3A4/5 inducer (including but not limited to: e.g. bosentan, nafcillin, modafinil and phenobarbital), no dose adjustment of camizestrant is necessary. When co-administering camizestrant in combination with abemaciclib or palbociclib, the use of such moderate CYP3A4/5 inducers should be avoided by switching to an alternate concomitant drug product (see section 5.2). CYP3A4/5 inhibitors In a clinical study, concomitant use of itraconazole, a strong CYP3A4/5 inhibitor, increased camizestrant geometric mean Cmax and AUCinf by 1.37-fold and 1.90-fold, respectively. Camizestrant in combination with ribociclib should be avoided in patients taking strong CYP3A4/5 inhibitors. In addition, caution should be exercised when combining camizestrant and ribociclib in combination with weak (e.g., chlorzoxazone and fosaprepitant) and moderate (e.g., aprepitant and diltiazem) CYP3A4/5 inhibitors. 5 Effects of camizestrant on other medicinal products CYP2C9 and CYP2C19 substrates In vitro data in conjunction with mechanistic static modelling show that camizestrant is a potent irreversible, time-dependent inhibitor of both CYP2C9 and CYP2C19. This means that the inhibition is irreversible and in order to reinstate functionality, the enzymes need to be synthesised again. Therefore, camizestrant is expected to increase the exposure levels of medicinal produc

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HOS-100960 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential Based on its mechanism of action and preclinical data, camizestrant may cause foetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving camizestrant. A pregnancy test should be performed and verified as negative on women of childbearing potential prior to initiating treatment and re-testing should be considered throughout treatment. Contraception in males and females Women of childbearing potential and men with women partners of childbearing potential have to use effective contraception during treatment with camizestrant and for the following periods after completion of treatment with camizestrant: at least 4 weeks for females and 1 week for males. Pregnancy There are no data from the use of camizestrant in pregnant women. Studies in animals have shown reproductive toxicity, including embryo lethality and dystocia (see section 5.3). Based on animal data and its mechanism of action, camizestrant should not be used during pregnancy unless the clinical condition of the women requires treatment with camizestrant. Breast-feeding It is not known whether camizestrant and its metabolites are excreted in human milk. Based on animal data (see section 5.3), a risk to the breast-fed child cannot be excluded. Breast-feeding must be discontinued prior to treatment with camizestrant and must not be resumed until 4 weeks following the last dose (see section 4.3). Fertility There are no data on the effect of camizestrant on human fertility. Results from animal studies have shown that camizestrant has marked effects on male and female reproductive organs in mice, rats and dogs and functional effects on female and male fertility in rats (see section 5.3).

HOS-100958 · has-warning-information · PDF-Seite 5

Bradycardia, when combined with medicinal products known to increase the risk of QTc prolongation Bradycardia and QTc prolongation have been reported with camizestrant and CDK4/6 inhibitor combination treatment (see section 4.8). A non-fatal Torsades de Pointes was observed in a patient with bradycardia and QTc prolongation for camizestrant in combination with ribociclib. Considering bradycardia in the context of potential QTc prolongation may increase the risk of arrhythmia, caution should be exercised when administering camizestrant in combination with agents known to cause QTc prolongation, e.g. ribociclib. Refer to monitoring recommendations (see section 4.2). Hepatic impairment Camizestrant is metabolised by the liver. Patients with impaired hepatic function are expected to have increased exposure to camizestrant. As a precautionary measure, the use of camizestrant in patients with moderate and severe hepatic impairment should be avoided. Patients with mild hepatic impairment are allowed to take camizestrant. No dose adjustment of camizestrant is required for patients with mild (NCI criteria) hepatic impairment (see sections 4.2 and 5.2). Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.