Leitlinien & Arzneimittelsicherheit

HOS-098074 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The most commonly occurring adverse reactions are diarrhoea, infections, neutropenia, leukopenia, anaemia, fatigue, nausea, vomiting, alopecia and decreased appetite. Of the most common adverse reactions, Grade ≥ 3 events were less than 5 % with the exception of neutropenia, leukopenia, and diarrhoea. Tabulated list of adverse reactions In the following table, adverse reactions are listed in order of MedDRA body system organ class and frequency. Frequency gradings are: 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 8. Adverse reactions reported in the phase 3 studies of abemaciclib in combination with endocrine therapya (N = 3 559) and during post-marketing experience System organ class Very common Common Uncommon Rare Infections and Infections b infestations Blood and lymphatic Neutropenia Febrile system disorders Leukopenia neutropenia e Anaemia Thrombocytopenia Lymphopenia h Metabolism and Decreased appetite nutrition disorders Nervous system Headache f disorders Dysgeusia g Dizziness g Eye disorders Lacrimation Photopsia increased Keratitis Vascular disorders Venous thromboembolism c Respiratory, thoracic ILD/pneumonitis d and mediastinal disorders Gastrointestinal Diarrhoea Dyspepsia f disorders Vomiting Nausea Stomatitis f Skin and subcutaneous Alopecia g Nail disorder f Erythema tissue disorders Pruritus g Dry skin e multiforme

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HOS-098070 · has-contraindication-information · PDF-Seite 7

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

HOS-098069 · has-indication-information · PDF-Seite 3

Early breast cancer Verzenios in combination with endocrine therapy is indicated for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive early breast cancer at high risk of recurrence (see section 5.1). In pre- or perimenopausal women, aromatase inhibitor endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist. Advanced or metastatic breast cancer Verzenios is indicated for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a LHRH agonist.

HOS-098072 · has-interaction-information · PDF-Seite 8

Effects of other medicinal products on the pharmacokinetics of abemaciclib Abemaciclib is primarily metabolised by CYP3A4. CYP3A4 inhibitors Co-administration of abemaciclib with CYP3A4 inhibitors can increase plasma concentrations of abemaciclib. In patients with advanced and/or metastatic cancer, co-administration of the CYP3A4 inhibitor clarithromycin resulted in a 3.4-fold increase in the plasma exposure of abemaciclib and a 2.5-fold increase in the combined unbound potency adjusted plasma exposure of abemaciclib and its active metabolites. Use of strong CYP3A4 inhibitors together with abemaciclib should be avoided. If strong CYP3A4 inhibitors need to be co-administered, the dose of abemaciclib should be reduced (see section 4.2), followed by careful monitoring of toxicity. Examples of strong CYP3A4 inhibitors include, but not limited to: clarithromycin, itraconazole, ketoconazole, lopinavir/ritonavir, posaconazole or voriconazole. Avoid grapefruit or grapefruit juice. No dose adjustment is necessary for patients treated with moderate or weak CYP3A4 inhibitors. There should, however, be close monitoring for signs of toxicity. CYP3A4 inducers Co-administration of abemaciclib with the strong CYP3A4 inducer rifampicin decreased the plasma concentration of abemaciclib by 95 % and unbound potency adjusted plasma concentration of abemaciclib plus its active metabolites by 77 % based on AUC0-∞. Concomitant use of strong CYP3A4 inducers (including, but not limited to: carbamazepine, phenytoin, rifampicin and St. John’s wort) should be avoided due to the risk of decreased efficacy of abemaciclib. 8 Effects of abemaciclib on the pharmacokinetics of other medicinal products Medicinal products that are substrates of transporters Abemaciclib and its major active metabolites inhibit the renal transporters organic cation transporter 2 (OCT2), multidrug and extrusion toxin protein (MATE1), and MATE2-K. In vivo interactions of abemaciclib with clinically relevant substrates of these transporters, such as dofetilide or creatinine, may occur (see section 4.8). In a clinical drug interaction study with metformin (substrate of OCT2, MATE1 and 2) co-administered with 400 mg abemaciclib, a small but not clinically relevant increase (37 %) in metformin plasma exposure was observed. This was found to be due to reduced renal secretion with unaffected glomerular filtration. In healthy subjects, co-administration of

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HOS-098073 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential/Contraception in females Women of childbearing potential should use highly effective contraception methods (e.g. double-barrier contraception) during treatment and for at least 3 weeks after completing therapy (see section 4.5). Pregnancy There are no data from the use of abemaciclib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Verzenios is not recommended during pregnancy and in women of child-bearing potential not using contraception. Breast-feeding It is unknown whether abemaciclib is excreted in human milk. A risk to breast-feeding children cannot be excluded. Patients receiving abemaciclib should not breast-feed. Fertility The effect of abemaciclib on fertility in humans is unknown. While in rats no effects on male fertility were noted, cytotoxic effects to the male reproductive tract in mice, rats, and dogs indicate that abemaciclib may impair fertility in males. No adverse effects on female reproductive organs in mice, rats, or dogs, nor effects on female fertility and early embryonic development in rats were observed (see section 5.3).

HOS-098071 · has-warning-information · PDF-Seite 7

Neutropenia Neutropenia was reported in patients receiving abemaciclib. Dose modification is recommended for patients who develop Grade 3 or 4 neutropenia (see section 4.2). Fatal events of neutropenic sepsis occurred in < 1 % of patients with metastatic breast cancer. Patients should be instructed to report any episode of fever to their healthcare provider. Infections/infestations Infections were reported in patients receiving abemaciclib plus endocrine therapy at a higher rate than in patients treated with endocrine therapy. Lung infection was reported in patients receiving abemaciclib without concurrent neutropenia. Fatal events occurred in < 1 % of patients with metastatic breast cancer. Patients should be monitored for signs and symptoms of infection and treated as medically appropriate. Venous thromboembolism Venous thromboembolic events were reported in patients treated with abemaciclib plus endocrine therapy. Patients should be monitored for signs and symptoms of deep vein thrombosis and pulmonary embolism and treated as medically appropriate. Based on the grade of VTE, abemaciclib may require dose modification (see section 4.2). Arterial Thromboembolic Events A potential increased risk for serious arterial thromboembolic events (ATEs), including ischemic stroke and myocardial infarction, has been observed in metastatic breast cancer studies when abemaciclib was administered in combination with endocrine therapies. The benefits and risks of continuing abemaciclib in patients who experience a serious ATE should be considered. Increased aminotransferases Increases in ALT and AST were reported in patients receiving abemaciclib. Based on the level of ALT or AST elevation, abemaciclib may require dose modification (see section 4.2). Diarrhoea Diarrhoea is the most common adverse reaction. Across clinical studies, median time to onset of the first diarrhoea event was approximately 6 to 8 days, and median duration of diarrhoea was 7 to 12 days (Grade 2) and 5 to 8 days (Grade 3). Diarrhoea can be associated with dehydration. Patients should start treatment with antidiarrhoeal agents such as loperamide at the first sign of loose stools, increase oral fluids and notify their healthcare provider. Dose modification is recommended for patients who develop ≥ Grade 2 diarrhoea (see section 4.2). 7 ILD/Pneumonitis ILD/pneumonitis was reported in patients receiving abemaciclib. Patients should be

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