Kisqali · 4.4 Special warnings and precautions for use · 1

HOS-097867 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile Early breast cancer The most common adverse drug reactions (ADRs) (reported at a frequency ≥20%) in the dataset for which the frequency for Kisqali plus aromatase inhibitor (AI) exceeds the frequency for AI alone were neutropenia, infections, nausea, headache, fatigue, leukopenia and abnormal liver function tests. The most common grade 3/4 ADRs (reported at a frequency of ≥2%) in the dataset for which the frequency for Kisqali plus AI exceeds the frequency for AI alone were neutropenia, abnormal liver function tests and leukopenia. Dose reduction due to adverse events, regardless of causality, occurred in 22.8% of patients receiving Kisqali plus AI in the phase III clinical study. Permanent discontinuation was reported in 19.7% of patients receiving Kisqali plus AI in the phase III clinical study. Advanced or metastatic breast cancer The most common adverse drug reactions (ADRs) (reported at a frequency ≥20%) in the pooled dataset for which the frequency for Kisqali plus any combination exceeds the frequency for placebo plus any combination were neutropenia, infections, nausea, fatigue, diarrhoea, leukopenia, vomiting, headache, constipation, alopecia, cough, rash, back pain, anaemia and abnormal liver function tests. The most common grade 3/4 ADRs (reported at a frequency of >2%) in the pooled dataset for which the frequency for Kisqali plus any combination exceeds the frequency for placebo plus any combination were neutropenia, leukopenia, abnormal liver function tests, lymphopenia, infections, back pain, anaemia, fatigue, hypophosphataemia and vomiting. Dose reduction due to adverse events, regardless of causality, occurred in 39.5% of patients receiving Kisqali in the phase III clinical studies regardless of the combination. Permanent discontinuation was reported in 8.7% of patients receiving Kisqali and any combination in the phase III clinical studies. Tabulated list of adverse reactions Early breast cancer The overall safety evaluation of Kisqali is based on the dataset from 2 525 patients who received Kisqali in combination with AI and who were included in the randomised, open-label phase III clinical study NATALEE. The median duration of exposure to ribociclib across the study was 33.0 months, with 69.4% patients exposed for >24 months, and 42.8% patients completing the 36-month ribociclib regimen. Advanced or metastatic breast cancer The overall safety evaluation of Kisqali is based on the pooled dataset fr

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HOS-097863 · has-contraindication-information · PDF-Seite 7

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

HOS-097862 · has-indication-information · PDF-Seite 2

Early breast cancer Kisqali in combination with an aromatase inhibitor is indicated for the adjuvant treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer at high risk of recurrence (see section 5.1 for selection criteria). In pre- or perimenopausal women, or in men, the aromatase inhibitor should be combined with a luteinising hormone-releasing hormone (LHRH) agonist. Advanced or metastatic breast cancer Kisqali is indicated for the treatment of women with HR-positive, 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-097865 · has-interaction-information · PDF-Seite 9

Substances that may increase ribociclib plasma concentrations Ribociclib is primarily metabolised by CYP3A4. Therefore, medicinal products that can influence CYP3A4 enzyme activity may alter the pharmacokinetics of ribociclib. Co-administration of the strong CYP3A4 inhibitor ritonavir (100 mg twice daily for 14 days) with a single 400 mg dose of ribociclib increased ribociclib exposure (AUCinf) and the peak concentration (Cmax) in healthy subjects 3.2- and 1.7-fold, respectively, relative to a single 400 mg ribociclib dose given alone. Cmax and AUClast for LEQ803 (a prominent metabolite of ribociclib accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively. Physiologically-based pharmacokinetic (PBPK) simulations with co-administered ritonavir (100 mg twice daily) estimated that the steady-state Cmax and AUC0-24h of ribociclib (400 mg once daily) increased by 1.5- and 1.8-fold, respectively. 9 The concomitant use of strong CYP3A4 inhibitors including, but not limited to, the following must be avoided: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, verapamil and voriconazole (see section 4.4). Alternative concomitant medicinal products with less potential to inhibit CYP3A4 should be considered and patients should be monitored for ribociclib-related ARs (see sections 4.2, 4.4 and 5.2). If co-administration of Kisqali with a strong CYP3A4 inhibitor cannot be avoided, the dose of Kisqali should be changed as described in section 4.2. However, there are no clinical data with these dose adjustments. Due to inter-patient variability, the recommended dose adjustments may not be optimal in all patients, therefore close monitoring for ribociclib-related ARs is recommended. In the event of ribociclib-related toxicity, the dose should be modified or treatment should be interrupted until toxicity is resolved (see sections 4.2 and 5.2). If the strong CYP3A4 inhibitor is discontinued, and after at least 5 half-lives of the CYP3A4 inhibitor (refer to the SmPC of the CYP3A4 inhibitor in question), Kisqali should be resumed at the same dose used prior to the initiation of the strong CYP3A4 inhibitor. PBPK simulations suggested that at a 600 mg dose of ribociclib, a moderate CYP3A4 inhibitor (erythromycin) may increase ribociclib steady-state Cmax and AUC 1.1- and 1.1-fold, respective

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HOS-097866 · has-pregnancy-information · PDF-Seite 12

Women of childbearing potential/Contraception Pregnancy status should be verified prior to starting treatment with Kisqali. Women of childbearing potential who are receiving Kisqali should use effective contraception (e.g. double-barrier contraception) during therapy and for at least 21 days after stopping treatment with Kisqali. Pregnancy There are no adequate and well-controlled studies in pregnant women. Based on findings in animals, ribociclib can cause foetal harm when administered to a pregnant woman (see section 5.3). Kisqali is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is not known if ribociclib is present in human milk. There are no data on the effects of ribociclib on the breast-fed infant or the effects of ribociclib on milk production. Ribociclib and its metabolites readily passed into the milk of lactating rats. Patients receiving Kisqali should not breast-feed for at least 21 days after the last dose. Fertility There are no clinical data available regarding effects of ribociclib on fertility. Based on animal studies, ribociclib may impair fertility in males of reproductive potential (see section 5.3).

HOS-097864 · has-warning-information · PDF-Seite 7

Critical visceral disease A longer time to response (TTR) has been observed in patients treated with ribociclib plus a non- steroidal aromatase inhibitor (NSAI) compared to those treated with combination chemotherapy in a clinical study (see section 5.1). This should be considered by the treating physician managing patients with critical visceral disease who may be considered for ribociclib plus NSAI therapy. Neutropenia Based on the severity of the neutropenia, treatment with Kisqali may have to be interrupted, reduced or discontinued as described in Table 2 (see sections 4.2 and 4.8). Hepatobiliary toxicity Liver function tests should be performed before initiating treatment with Kisqali. After initiating treatment, liver function should be monitored (see sections 4.2 and 4.8). Based on the severity of the transaminase elevations, treatment with Kisqali may have to be interrupted, reduced or discontinued as described in Table 3 (see sections 4.2 and 4.8). Recommendations for patients who have elevated AST/ALT grade ≥ 3 at baseline have not been established. 7 QT interval prolongation The use of Kisqali should be avoided in patients who already have or who are at significant risk of developing QTc prolongation. This includes patients: • with long QT syndrome; • with uncontrolled or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmias; • with electrolyte abnormalities. The use of Kisqali with medicinal products known to prolong QTc interval and/or strong CYP3A4 inhibitors should be avoided as this may lead to clinically meaningful prolongation of the QTcF interval (see sections 4.2, 4.5 and 5.1). If co-administration of Kisqali with a strong CYP3A4 inhibitor cannot be avoided, the Kisqali dose should be changed as described in section 4.2. Based on the findings from study E2301 (MONALEESA-7), Kisqali is not recommended for use in combination with tamoxifen (see sections 4.8 and 5.1). Early breast cancer In study O12301C (NATALEE), a QTcF interval increase >60 msec from baseline was observed in 19 (0.8%) patients receiving Kisqali plus AI. ECG should be assessed before initiating treatment. Treatment with Kisqali should be initiated only in patients with QTcF values less than 450 msec. ECG should be repeated at approximately day 14 of the first cycle, then as clinically indicated (see sections 4

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